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10.1007%2Fs00018-019-03174-6
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mmps and adams and their function in the cns
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These metalloproteinases are involved in many neurological conditions but also contribute crucially to neurophysiological functions, such as synaptic plasticity and neuroregeneration via regulating stem cell biology and remyelination [>>1<<]. Until now, 24 different mammalian MMPs are described, while each type has a defined substrate specificity [2].
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Until now, 24 different mammalian MMPs are described, while each type has a defined substrate specificity [>>2<<]. Collectively, MMPs can degrade all components of the extracellular matrix (ECM) [1, 3]. Apart from degrading ECM, MMPs are also able to cleave adhesion molecules, receptors and growth factors [4], indicating an involvement of MMPs in
n2:mentions
n3:11687497
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Collectively, MMPs can degrade all components of the extracellular matrix (ECM) [>>1<<, 3]. Apart from degrading ECM, MMPs are also able to cleave adhesion molecules, receptors and growth factors [4], indicating an involvement of MMPs in cell migration, signaling, differentiation, cell survival or apoptosis, angiogenesis
n2:mentions
n3:16288297
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Collectively, MMPs can degrade all components of the extracellular matrix (ECM) [1, >>3<<]. Apart from degrading ECM, MMPs are also able to cleave adhesion molecules, receptors and growth factors [4], indicating an involvement of MMPs in cell migration, signaling, differentiation, cell survival or apoptosis, angiogenesis and
n2:mentions
n3:15363807
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Apart from degrading ECM, MMPs are also able to cleave adhesion molecules, receptors and growth factors [>>4<<], indicating an involvement of MMPs in cell migration, signaling, differentiation, cell survival or apoptosis, angiogenesis and inflammation [1, 2, 5].
n2:mentions
n3:11544020
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degrading ECM, MMPs are also able to cleave adhesion molecules, receptors and growth factors [4], indicating an involvement of MMPs in cell migration, signaling, differentiation, cell survival or apoptosis, angiogenesis and inflammation [>>1<<, 2, 5]. ADAMs also have the capacity to degrade and remodel components of the ECM, but their best characterized function is protein ectodomain shedding, thereby processing and releasing mature proteins (e.g., TNF-α) from membrane-anchored
n2:mentions
n3:16288297
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ECM, MMPs are also able to cleave adhesion molecules, receptors and growth factors [4], indicating an involvement of MMPs in cell migration, signaling, differentiation, cell survival or apoptosis, angiogenesis and inflammation [1, >>2<<, 5]. ADAMs also have the capacity to degrade and remodel components of the ECM, but their best characterized function is protein ectodomain shedding, thereby processing and releasing mature proteins (e.g., TNF-α) from membrane-anchored
n2:mentions
n3:11687497
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ECM, MMPs are also able to cleave adhesion molecules, receptors and growth factors [4], indicating an involvement of MMPs in cell migration, signaling, differentiation, cell survival or apoptosis, angiogenesis and inflammation [1, 2, >>5<<]. ADAMs also have the capacity to degrade and remodel components of the ECM, but their best characterized function is protein ectodomain shedding, thereby processing and releasing mature proteins (e.g., TNF-α) from membrane-anchored
n2:mentions
n3:15286728
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_:vb94664039
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also have the capacity to degrade and remodel components of the ECM, but their best characterized function is protein ectodomain shedding, thereby processing and releasing mature proteins (e.g., TNF-α) from membrane-anchored precursors [>>1<<, 6]. During pathological conditions of the central nervous system (CNS), metalloproteinases derive from infiltrating leukocytes (neutrophils, macrophages and lymphocytes) or brain-resident cells (microglia, astrocytes and neurons) [7].
n2:mentions
n3:16288297
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_:vb94664040
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have the capacity to degrade and remodel components of the ECM, but their best characterized function is protein ectodomain shedding, thereby processing and releasing mature proteins (e.g., TNF-α) from membrane-anchored precursors [1, >>6<<]. During pathological conditions of the central nervous system (CNS), metalloproteinases derive from infiltrating leukocytes (neutrophils, macrophages and lymphocytes) or brain-resident cells (microglia, astrocytes and neurons) [7].
n2:mentions
n3:14519395
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_:vb94664041
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During pathological conditions of the central nervous system (CNS), metalloproteinases derive from infiltrating leukocytes (neutrophils, macrophages and lymphocytes) or brain-resident cells (microglia, astrocytes and neurons) [>>7<<].
n2:mentions
n3:11433375
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_:vb94664042
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As metalloproteinases have the capacity for extensive tissue destruction, their activity is tightly regulated and controlled [>>1<<, 8]. The catalytic activity of MMPs is regulated on four different levels; namely gene expression, compartmentalization, pro-enzyme activation and enzyme inhibition [5].
n2:mentions
n3:16288297
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_:vb94664043
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As metalloproteinases have the capacity for extensive tissue destruction, their activity is tightly regulated and controlled [1, >>8<<]. The catalytic activity of MMPs is regulated on four different levels; namely gene expression, compartmentalization, pro-enzyme activation and enzyme inhibition [5].
n2:mentions
n3:12209155
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The catalytic activity of MMPs is regulated on four different levels; namely gene expression, compartmentalization, pro-enzyme activation and enzyme inhibition [>>5<<]. Pro-MMPs are kept in a catalytically inactive state and can be activated by proteolytic cleavage of the pro-domain or by modification of the pro-domain’s cysteine thiol group [5, 9]. Of importance for inflammatory and infectious
n2:mentions
n3:15286728
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Pro-MMPs are kept in a catalytically inactive state and can be activated by proteolytic cleavage of the pro-domain or by modification of the pro-domain’s cysteine thiol group [>>5<<, 9]. Of importance for inflammatory and infectious processes, reactive oxygen species (ROS) have the potential to activate MMPs via oxidation of the pro-domain’s thiol group [10–12]. MMP inactivation might be achieved be natural
n2:mentions
n3:15286728
Subject Item
_:vb94664046
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Pro-MMPs are kept in a catalytically inactive state and can be activated by proteolytic cleavage of the pro-domain or by modification of the pro-domain’s cysteine thiol group [5, >>9<<]. Of importance for inflammatory and infectious processes, reactive oxygen species (ROS) have the potential to activate MMPs via oxidation of the pro-domain’s thiol group [10–12]. MMP inactivation might be achieved be natural inhibitors,
n2:mentions
n3:2164689
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_:vb94664047
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Of importance for inflammatory and infectious processes, reactive oxygen species (ROS) have the potential to activate MMPs via oxidation of the pro-domain’s thiol group [>>10<<–12]. MMP inactivation might be achieved be natural inhibitors, of which the tissue inhibitors of metalloproteinases (TIMPs) are the most prominent ones. By binding to the catalytic site of MMPs, the four TIMPs (TIMP-1, -2, -3 and -4) are
n2:mentions
n3:3012563 n3:2982211 n3:11533038
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By binding to the catalytic site of MMPs, the four TIMPs (TIMP-1, -2, -3 and -4) are able to terminate MMP activity [>>5<<, 13]. Many TIMPs target multiple metalloproteinases, but there are also some strict specificities such as TIMP-3, which is the only TIMP to inhibit ADAM17 [14, 15].
n2:mentions
n3:15286728
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By binding to the catalytic site of MMPs, the four TIMPs (TIMP-1, -2, -3 and -4) are able to terminate MMP activity [5, >>13<<]. Many TIMPs target multiple metalloproteinases, but there are also some strict specificities such as TIMP-3, which is the only TIMP to inhibit ADAM17 [14, 15].
n2:mentions
n3:12730128
Subject Item
_:vb94664050
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Many TIMPs target multiple metalloproteinases, but there are also some strict specificities such as TIMP-3, which is the only TIMP to inhibit ADAM17 [14, >>15<<].
n2:mentions
n3:23969736
Subject Item
_:vb94664051
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dc:title
effect of metalloproteinases on bbb integrity
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(BBB) integrity was demonstrated for the first time in the early 1990s by inducing BBB breakdown after intracerebroventricular administration of MMP-2 and MMP-9, an effect that was prevented by simultaneous administration of TIMP-2 [>>16<<–18]. Subsequent findings of elevated MMP-9 levels after cerebral insults for the first time established a link between MMPs and inflammation in the CNS [18, 19].
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Subsequent findings of elevated MMP-9 levels after cerebral insults for the first time established a link between MMPs and inflammation in the CNS [>>18<<, 19]. Intracerebral injection of lipopolysaccharide (LPS)—mimicking bacterial brain infections—increased MMP-2, MMP-3 and TNF-α mRNA levels [20] and induced BBB disruption through the action of MMP-9 [21].
n2:mentions
n3:25410364
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Subsequent findings of elevated MMP-9 levels after cerebral insults for the first time established a link between MMPs and inflammation in the CNS [18, >>19<<]. Intracerebral injection of lipopolysaccharide (LPS)—mimicking bacterial brain infections—increased MMP-2, MMP-3 and TNF-α mRNA levels [20] and induced BBB disruption through the action of MMP-9 [21].
n2:mentions
n3:8719627
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Intracerebral injection of lipopolysaccharide (LPS)—mimicking bacterial brain infections—increased MMP-2, MMP-3 and TNF-α mRNA levels [>>20<<] and induced BBB disruption through the action of MMP-9 [21].
n2:mentions
n3:11929634
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Intracerebral injection of lipopolysaccharide (LPS)—mimicking bacterial brain infections—increased MMP-2, MMP-3 and TNF-α mRNA levels [20] and induced BBB disruption through the action of MMP-9 [>>21<<].
n2:mentions
n3:9644031
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Blood–brain barrier opening is associated with a morphological redistribution of tight junction (TJ) and adherens junction (AJ) proteins from the membrane to the cytoplasm [>>22<<]. In different neurological pathologies, MMPs are reported to degrade TJ and basal lamina proteins, thereby inducing BBB leakage with subsequent neutrophil infiltration, brain edema and hemorrhage [22, 23].
n2:mentions
n3:23565108
Subject Item
_:vb94664058
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In different neurological pathologies, MMPs are reported to degrade TJ and basal lamina proteins, thereby inducing BBB leakage with subsequent neutrophil infiltration, brain edema and hemorrhage [>>22<<, 23].
n2:mentions
n3:23565108
Subject Item
_:vb94664059
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In different neurological pathologies, MMPs are reported to degrade TJ and basal lamina proteins, thereby inducing BBB leakage with subsequent neutrophil infiltration, brain edema and hemorrhage [22, >>23<<].
n2:mentions
n3:16257222
Subject Item
_:vb94664060
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The role of MMP-2 in BBB opening was intensively studied in cerebral ischemia models, where MMP-2 was found to play an important role in the initial BBB opening [>>24<<] with increased activation of MMP-2 being associated with the degradation of the TJ proteins claudin-5 and occludin [17, 25].
n2:mentions
n3:9756602
Subject Item
_:vb94664061
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studied in cerebral ischemia models, where MMP-2 was found to play an important role in the initial BBB opening [24] with increased activation of MMP-2 being associated with the degradation of the TJ proteins claudin-5 and occludin [>>17<<, 25]. Both MMP-2 and MMP-9 (gelatinase A and B) are able to degrade the major components of the basal lamina (type IV collagen, laminin and fibronectin) surrounding the cerebral blood vessels, thus increasing BBB permeability [22].
n2:mentions
n3:1381261
Subject Item
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studied in cerebral ischemia models, where MMP-2 was found to play an important role in the initial BBB opening [24] with increased activation of MMP-2 being associated with the degradation of the TJ proteins claudin-5 and occludin [17, >>25<<]. Both MMP-2 and MMP-9 (gelatinase A and B) are able to degrade the major components of the basal lamina (type IV collagen, laminin and fibronectin) surrounding the cerebral blood vessels, thus increasing BBB permeability [22].
n2:mentions
n3:16850029
Subject Item
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Both MMP-2 and MMP-9 (gelatinase A and B) are able to degrade the major components of the basal lamina (type IV collagen, laminin and fibronectin) surrounding the cerebral blood vessels, thus increasing BBB permeability [>>22<<]. In vitro and in vivo, MMP-9 is capable of degrade claudin-5, occludin and ZO-1, thereby participating in TJ degradation [25–27]. Experimental data propose that MMP-9—which plays a profound role in delayed BBB breakdown [28]—derives
n2:mentions
n3:23565108
Subject Item
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In vitro and in vivo, MMP-9 is capable of degrade claudin-5, occludin and ZO-1, thereby participating in TJ degradation [>>25<<–27]. Experimental data propose that MMP-9—which plays a profound role in delayed BBB breakdown [28]—derives mostly from brain microvascular endothelial cells and infiltrating neutrophils [27, 29–32]. Infiltrating neutrophils contain
n2:mentions
n3:18799677 n3:19821483 n3:16850029
Subject Item
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Experimental data propose that MMP-9—which plays a profound role in delayed BBB breakdown [>>28<<]—derives mostly from brain microvascular endothelial cells and infiltrating neutrophils [27, 29–32].
n2:mentions
n3:18673209
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Experimental data propose that MMP-9—which plays a profound role in delayed BBB breakdown [28]—derives mostly from brain microvascular endothelial cells and infiltrating neutrophils [>>27<<, 29–32]. Infiltrating neutrophils contain stores of MMP-9—so-called tertiary granules (or gelatinase granules)—which are rapidly released upon entering the site of injury [1, 33, 34]. MMP-9 levels critically increase during bacterial
n2:mentions
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Experimental data propose that MMP-9—which plays a profound role in delayed BBB breakdown [28]—derives mostly from brain microvascular endothelial cells and infiltrating neutrophils [27, >>29<<–32]. Infiltrating neutrophils contain stores of MMP-9—so-called tertiary granules (or gelatinase granules)—which are rapidly released upon entering the site of injury [1, 33, 34]. MMP-9 levels critically increase during bacterial
n2:mentions
n3:14663338 n3:12717622 n3:20130219
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Infiltrating neutrophils contain stores of MMP-9—so-called tertiary granules (or gelatinase granules)—which are rapidly released upon entering the site of injury [>>1<<, 33, 34]. MMP-9 levels critically increase during bacterial meningitis and elevated MMP-9 levels are associated with BBB damage and neurological sequelae [32, 35]. In experimental ischemic stroke, increased neutrophil-derived MMP-9 is
n2:mentions
n3:16288297
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Infiltrating neutrophils contain stores of MMP-9—so-called tertiary granules (or gelatinase granules)—which are rapidly released upon entering the site of injury [1, >>33<<, 34]. MMP-9 levels critically increase during bacterial meningitis and elevated MMP-9 levels are associated with BBB damage and neurological sequelae [32, 35]. In experimental ischemic stroke, increased neutrophil-derived MMP-9 is
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n3:11574282
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Infiltrating neutrophils contain stores of MMP-9—so-called tertiary granules (or gelatinase granules)—which are rapidly released upon entering the site of injury [1, 33, >>34<<]. MMP-9 levels critically increase during bacterial meningitis and elevated MMP-9 levels are associated with BBB damage and neurological sequelae [32, 35]. In experimental ischemic stroke, increased neutrophil-derived MMP-9 is critically
n2:mentions
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n2:Context
rdf:value
MMP-9 levels critically increase during bacterial meningitis and elevated MMP-9 levels are associated with BBB damage and neurological sequelae [>>32<<, 35]. In experimental ischemic stroke, increased neutrophil-derived MMP-9 is critically involved in a state of systemic inflammation with sustained degradation of TJ and basal lamina proteins leading to exacerbated brain injury [22, 27].
n2:mentions
n3:12717622
Subject Item
_:vb94664072
rdf:type
n2:Context
rdf:value
MMP-9 levels critically increase during bacterial meningitis and elevated MMP-9 levels are associated with BBB damage and neurological sequelae [32, >>35<<]. In experimental ischemic stroke, increased neutrophil-derived MMP-9 is critically involved in a state of systemic inflammation with sustained degradation of TJ and basal lamina proteins leading to exacerbated brain injury [22, 27].
n2:mentions
n3:10913401
Subject Item
_:vb94664073
rdf:type
n2:Context
rdf:value
In experimental ischemic stroke, increased neutrophil-derived MMP-9 is critically involved in a state of systemic inflammation with sustained degradation of TJ and basal lamina proteins leading to exacerbated brain injury [>>22<<, 27]. Apart from these two gelatinases, other MMPs influence BBB integrity. MMP-3 is able to degrade laminin, gelatin, E-cadherin, proteoglycans and fibronectin [36] and has been demonstrated to mediate BBB opening after LPS-induced
n2:mentions
n3:23565108
Subject Item
_:vb94664074
rdf:type
n2:Context
rdf:value
In experimental ischemic stroke, increased neutrophil-derived MMP-9 is critically involved in a state of systemic inflammation with sustained degradation of TJ and basal lamina proteins leading to exacerbated brain injury [22, >>27<<]. Apart from these two gelatinases, other MMPs influence BBB integrity. MMP-3 is able to degrade laminin, gelatin, E-cadherin, proteoglycans and fibronectin [36] and has been demonstrated to mediate BBB opening after LPS-induced
n2:mentions
n3:18799677
Subject Item
_:vb94664075
rdf:type
n2:Context
rdf:value
MMP-3 is able to degrade laminin, gelatin, E-cadherin, proteoglycans and fibronectin [>>36<<] and has been demonstrated to mediate BBB opening after LPS-induced neuroinflammation, thereby facilitating neutrophil infiltration [37].
n2:mentions
n3:20640864
Subject Item
_:vb94664076
rdf:type
n2:Context
rdf:value
MMP-3 is able to degrade laminin, gelatin, E-cadherin, proteoglycans and fibronectin [36] and has been demonstrated to mediate BBB opening after LPS-induced neuroinflammation, thereby facilitating neutrophil infiltration [>>37<<]. Collagenases (MMP-1, -8 and -13) preferentially cleave helical collagens in the ECM [22] and are reported to be activated and/or upregulated in vessels with BBB impairment [38–40]. In bacterial meningitis, cerebrospinal fluid (CSF)
n2:mentions
n3:16624562
Subject Item
_:vb94664077
rdf:type
n2:Context
rdf:value
Collagenases (MMP-1, -8 and -13) preferentially cleave helical collagens in the ECM [>>22<<] and are reported to be activated and/or upregulated in vessels with BBB impairment [38–40].
n2:mentions
n3:23565108
Subject Item
_:vb94664078
rdf:type
n2:Context
rdf:value
Collagenases (MMP-1, -8 and -13) preferentially cleave helical collagens in the ECM [22] and are reported to be activated and/or upregulated in vessels with BBB impairment [>>38<<–40]. In bacterial meningitis, cerebrospinal fluid (CSF) levels of MMP-13 and MMP-8 are upregulated [41] and associated with BBB damage [35]. Repeated lumbar punctures in bacterial meningitis patients revealed that MMP-8 levels were
n2:mentions
n3:18985055 n3:19317417 n3:19300451
Subject Item
_:vb94664079
rdf:type
n2:Context
rdf:value
In bacterial meningitis, cerebrospinal fluid (CSF) levels of MMP-13 and MMP-8 are upregulated [>>41<<] and associated with BBB damage [35].
n2:mentions
n3:10430840
Subject Item
_:vb94664080
rdf:type
n2:Context
rdf:value
In bacterial meningitis, cerebrospinal fluid (CSF) levels of MMP-13 and MMP-8 are upregulated [41] and associated with BBB damage [>>35<<]. Repeated lumbar punctures in bacterial meningitis patients revealed that MMP-8 levels were regulated independently and did not correlate with CSF granulocyte cell counts, indicating that these MMPs might not only be secreted by
n2:mentions
n3:10913401
Subject Item
_:vb94664081
rdf:type
n2:Context
rdf:value
revealed that MMP-8 levels were regulated independently and did not correlate with CSF granulocyte cell counts, indicating that these MMPs might not only be secreted by infiltrating neutrophils but also from brain-resident cells [>>35<<].
n2:mentions
n3:10913401
Subject Item
_:vb94664082
rdf:type
n2:Context
rdf:value
ADAM12 and ADAM17 were shown to control neural vascular barrier function upon hypoxic stimuli by diminishing claudin-5 in brain microvascular endothelial cells, an effect that was prevented by specific inhibition of ADAM12 or ADAM17 [>>42<<]. Activated ADAM10 cleaves VE-cadherin and promotes leukocyte migration to inter-endothelial junctions [43, 44].
n2:mentions
n3:26242473
Subject Item
_:vb94664083
rdf:type
n2:Context
rdf:value
Activated ADAM10 cleaves VE-cadherin and promotes leukocyte migration to inter-endothelial junctions [>>43<<, 44].
n2:mentions
n3:21926978
Subject Item
_:vb94664084
rdf:type
n2:Context
rdf:value
Activated ADAM10 cleaves VE-cadherin and promotes leukocyte migration to inter-endothelial junctions [43, >>44<<].
n2:mentions
n3:18497310
Subject Item
_:vb94664085
rdf:type
n5:Section
dc:title
mmps and adams in progression of neuroinflammation
n5:contains
_:vb94664112 _:vb94664113 _:vb94664114 _:vb94664115 _:vb94664116 _:vb94664117 _:vb94664118 _:vb94664119 _:vb94664120 _:vb94664121 _:vb94664122 _:vb94664123 _:vb94664124 _:vb94664125 _:vb94664126 _:vb94664127 _:vb94664096 _:vb94664097 _:vb94664098 _:vb94664099 _:vb94664100 _:vb94664101 _:vb94664102 _:vb94664103 _:vb94664104 _:vb94664105 _:vb94664106 _:vb94664107 _:vb94664108 _:vb94664109 _:vb94664110 _:vb94664111 _:vb94664086 _:vb94664087 _:vb94664088 _:vb94664089 _:vb94664090 _:vb94664091 _:vb94664092 _:vb94664093 _:vb94664094 _:vb94664095 _:vb94664176 _:vb94664177 _:vb94664178 _:vb94664179 _:vb94664180 _:vb94664181 _:vb94664182 _:vb94664183 _:vb94664184 _:vb94664185 _:vb94664186 _:vb94664187 _:vb94664188 _:vb94664189 _:vb94664190 _:vb94664191 _:vb94664160 _:vb94664161 _:vb94664162 _:vb94664163 _:vb94664164 _:vb94664165 _:vb94664166 _:vb94664167 _:vb94664168 _:vb94664169 _:vb94664170 _:vb94664171 _:vb94664172 _:vb94664173 _:vb94664174 _:vb94664175 _:vb94664144 _:vb94664145 _:vb94664146 _:vb94664147 _:vb94664148 _:vb94664149 _:vb94664150 _:vb94664151 _:vb94664152 _:vb94664153 _:vb94664154 _:vb94664155 _:vb94664156 _:vb94664157 _:vb94664158 _:vb94664159 _:vb94664128 _:vb94664129 _:vb94664130 _:vb94664131 _:vb94664132 _:vb94664133 _:vb94664134 _:vb94664135 _:vb94664136 _:vb94664137 _:vb94664138 _:vb94664139 _:vb94664140 _:vb94664141 _:vb94664142 _:vb94664143 _:vb94664208 _:vb94664209 _:vb94664210 _:vb94664211 _:vb94664212 _:vb94664213 _:vb94664214 _:vb94664192 _:vb94664193 _:vb94664194 _:vb94664195 _:vb94664196 _:vb94664197 _:vb94664198 _:vb94664199 _:vb94664200 _:vb94664201 _:vb94664202 _:vb94664203 _:vb94664204 _:vb94664205 _:vb94664206 _:vb94664207
Subject Item
_:vb94664086
rdf:type
n2:Context
rdf:value
As the first described MMP was found to degrade collagen [>>45<<], the following contributions on MMPs mostly focused on their ability to degrade ECM components [5].
n2:mentions
n3:13902219
Subject Item
_:vb94664087
rdf:type
n2:Context
rdf:value
As the first described MMP was found to degrade collagen [45], the following contributions on MMPs mostly focused on their ability to degrade ECM components [>>5<<]. More recent data suggest, however, that MMPs have a much wider range of activity, including non-matrix substrates [4].
n2:mentions
n3:15286728
Subject Item
_:vb94664088
rdf:type
n2:Context
rdf:value
More recent data suggest, however, that MMPs have a much wider range of activity, including non-matrix substrates [>>4<<]. Instead of clustering MMPs together for their function in ECM degradation, Parks et al. suggest to categorize them rather according to their role in inflammation [5]. Table 1 and Fig. 1 summarize functions of selected metalloproteinases
n2:mentions
n3:11544020
Subject Item
_:vb94664089
rdf:type
n2:Context
rdf:value
Instead of clustering MMPs together for their function in ECM degradation, Parks et al. suggest to categorize them rather according to their role in inflammation [>>5<<]. Table 1 and Fig. 1 summarize functions of selected metalloproteinases in pro- and anti-inflammatory processes.Table
n2:mentions
n3:15286728
Subject Item
_:vb94664090
rdf:type
n2:Context
rdf:value
Metallo-proteinaseCommon nameSubstrateBiological function during inflammationReferencesMMP-1Collagenase-1CCL7, MCP-1,-2,-4Regulation of chemokine signaling[>>48<<]CXCL12 (SDF-1α)[49]MMP-2Gelatinase ACCL7 (MCP3)Regulation of chemokine signaling[47]CXCL12 (SDF-1α)Chemotactic gradient[49](CCL11 gradient)[57]pIL-1βIL-1β activation[62]Claudin-5, occludinJunction protein degradation[17,
n2:mentions
n3:12149192
Subject Item
_:vb94664091
rdf:type
n2:Context
rdf:value
Metallo-proteinaseCommon nameSubstrateBiological function during inflammationReferencesMMP-1Collagenase-1CCL7, MCP-1,-2,-4Regulation of chemokine signaling[48]CXCL12 (SDF-1α)[>>49<<]MMP-2Gelatinase ACCL7 (MCP3)Regulation of chemokine signaling[47]CXCL12 (SDF-1α)Chemotactic gradient[49](CCL11 gradient)[57]pIL-1βIL-1β activation[62]Claudin-5, occludinJunction protein degradation[17, 25]MMP-3Stromelysin-1CCL7,
n2:mentions
n3:11571304
Subject Item
_:vb94664092
rdf:type
n2:Context
rdf:value
nameSubstrateBiological function during inflammationReferencesMMP-1Collagenase-1CCL7, MCP-1,-2,-4Regulation of chemokine signaling[48]CXCL12 (SDF-1α)[49]MMP-2Gelatinase ACCL7 (MCP3)Regulation of chemokine signaling[>>47<<]CXCL12 (SDF-1α)Chemotactic gradient[49](CCL11 gradient)[57]pIL-1βIL-1β activation[62]Claudin-5, occludinJunction protein degradation[17, 25]MMP-3Stromelysin-1CCL7, MCP-1,-2,-4Regulation of chemokine signaling[48]CXCL12
n2:mentions
n3:10947989
Subject Item
_:vb94664093
rdf:type
n2:Context
rdf:value
function during inflammationReferencesMMP-1Collagenase-1CCL7, MCP-1,-2,-4Regulation of chemokine signaling[48]CXCL12 (SDF-1α)[49]MMP-2Gelatinase ACCL7 (MCP3)Regulation of chemokine signaling[47]CXCL12 (SDF-1α)Chemotactic gradient[>>49<<](CCL11 gradient)[57]pIL-1βIL-1β activation[62]Claudin-5, occludinJunction protein degradation[17, 25]MMP-3Stromelysin-1CCL7, MCP-1,-2,-4Regulation of chemokine signaling[48]CXCL12 (SDF-1α)[49]pIL-1βIL-1β activation[62]Latent TGF-β1Pot.
n2:mentions
n3:11571304
Subject Item
_:vb94664094
rdf:type
n2:Context
rdf:value
inflammationReferencesMMP-1Collagenase-1CCL7, MCP-1,-2,-4Regulation of chemokine signaling[48]CXCL12 (SDF-1α)[49]MMP-2Gelatinase ACCL7 (MCP3)Regulation of chemokine signaling[47]CXCL12 (SDF-1α)Chemotactic gradient[49](CCL11 gradient)[>>57<<]pIL-1βIL-1β activation[62]Claudin-5, occludinJunction protein degradation[17, 25]MMP-3Stromelysin-1CCL7, MCP-1,-2,-4Regulation of chemokine signaling[48]CXCL12 (SDF-1α)[49]pIL-1βIL-1β activation[62]Latent TGF-β1Pot.
n2:mentions
n3:11887181
Subject Item
_:vb94664095
rdf:type
n2:Context
rdf:value
MCP-1,-2,-4Regulation of chemokine signaling[48]CXCL12 (SDF-1α)[49]MMP-2Gelatinase ACCL7 (MCP3)Regulation of chemokine signaling[47]CXCL12 (SDF-1α)Chemotactic gradient[49](CCL11 gradient)[57]pIL-1βIL-1β activation[>>62<<]Claudin-5, occludinJunction protein degradation[17, 25]MMP-3Stromelysin-1CCL7, MCP-1,-2,-4Regulation of chemokine signaling[48]CXCL12 (SDF-1α)[49]pIL-1βIL-1β activation[62]Latent TGF-β1Pot.
n2:mentions
n3:9759850
Subject Item
_:vb94664096
rdf:type
n2:Context
rdf:value
signaling[48]CXCL12 (SDF-1α)[49]MMP-2Gelatinase ACCL7 (MCP3)Regulation of chemokine signaling[47]CXCL12 (SDF-1α)Chemotactic gradient[49](CCL11 gradient)[57]pIL-1βIL-1β activation[62]Claudin-5, occludinJunction protein degradation[>>17<<, 25]MMP-3Stromelysin-1CCL7, MCP-1,-2,-4Regulation of chemokine signaling[48]CXCL12 (SDF-1α)[49]pIL-1βIL-1β activation[62]Latent TGF-β1Pot.
n2:mentions
n3:1381261
Subject Item
_:vb94664097
rdf:type
n2:Context
rdf:value
signaling[48]CXCL12 (SDF-1α)[49]MMP-2Gelatinase ACCL7 (MCP3)Regulation of chemokine signaling[47]CXCL12 (SDF-1α)Chemotactic gradient[49](CCL11 gradient)[57]pIL-1βIL-1β activation[62]Claudin-5, occludinJunction protein degradation[17, >>25<<]MMP-3Stromelysin-1CCL7, MCP-1,-2,-4Regulation of chemokine signaling[48]CXCL12 (SDF-1α)[49]pIL-1βIL-1β activation[62]Latent TGF-β1Pot.
n2:mentions
n3:16850029
Subject Item
_:vb94664098
rdf:type
n2:Context
rdf:value
of chemokine signaling[47]CXCL12 (SDF-1α)Chemotactic gradient[49](CCL11 gradient)[57]pIL-1βIL-1β activation[62]Claudin-5, occludinJunction protein degradation[17, 25]MMP-3Stromelysin-1CCL7, MCP-1,-2,-4Regulation of chemokine signaling[>>48<<]CXCL12 (SDF-1α)[49]pIL-1βIL-1β activation[62]Latent TGF-β1Pot.
n2:mentions
n3:12149192
Subject Item
_:vb94664099
rdf:type
n2:Context
rdf:value
(SDF-1α)Chemotactic gradient[49](CCL11 gradient)[57]pIL-1βIL-1β activation[62]Claudin-5, occludinJunction protein degradation[17, 25]MMP-3Stromelysin-1CCL7, MCP-1,-2,-4Regulation of chemokine signaling[48]CXCL12 (SDF-1α)[>>49<<]pIL-1βIL-1β activation[62]Latent TGF-β1Pot.
n2:mentions
n3:11571304
Subject Item
_:vb94664100
rdf:type
n2:Context
rdf:value
gradient[49](CCL11 gradient)[57]pIL-1βIL-1β activation[62]Claudin-5, occludinJunction protein degradation[17, 25]MMP-3Stromelysin-1CCL7, MCP-1,-2,-4Regulation of chemokine signaling[48]CXCL12 (SDF-1α)[49]pIL-1βIL-1β activation[>>62<<]Latent TGF-β1Pot.
n2:mentions
n3:9759850
Subject Item
_:vb94664101
rdf:type
n2:Context
rdf:value
anti-inflammatory response[>>68<<]E-cadherinJunction protein degradation[36]MMP-7MatrilysinSyndecan-1 (CXCL1 release)Chemotactic gradient[56]proTNFαTNF-α activation[65]MMP-8Collagenase-2LIXChemotactic gradient[52]CXCL6, CXCL5, LIXRegulation of chemokine
n2:mentions
n3:11907708
Subject Item
_:vb94664102
rdf:type
n2:Context
rdf:value
anti-inflammatory response[68]E-cadherinJunction protein degradation[>>36<<]MMP-7MatrilysinSyndecan-1 (CXCL1 release)Chemotactic gradient[56]proTNFαTNF-α activation[65]MMP-8Collagenase-2LIXChemotactic gradient[52]CXCL6, CXCL5, LIXRegulation of chemokine signaling[54]OccludinJunction protein
n2:mentions
n3:20640864
Subject Item
_:vb94664103
rdf:type
n2:Context
rdf:value
anti-inflammatory response[68]E-cadherinJunction protein degradation[36]MMP-7MatrilysinSyndecan-1 (CXCL1 release)Chemotactic gradient[>>56<<]proTNFαTNF-α activation[65]MMP-8Collagenase-2LIXChemotactic gradient[52]CXCL6, CXCL5, LIXRegulation of chemokine signaling[54]OccludinJunction protein degradation[131]MMP-9Gelatinase BCXCL8 (IL-8)Chemotactic gradient[46]CXCL12
n2:mentions
n3:12464176
Subject Item
_:vb94664104
rdf:type
n2:Context
rdf:value
anti-inflammatory response[68]E-cadherinJunction protein degradation[36]MMP-7MatrilysinSyndecan-1 (CXCL1 release)Chemotactic gradient[56]proTNFαTNF-α activation[>>65<<]MMP-8Collagenase-2LIXChemotactic gradient[52]CXCL6, CXCL5, LIXRegulation of chemokine signaling[54]OccludinJunction protein degradation[131]MMP-9Gelatinase BCXCL8 (IL-8)Chemotactic gradient[46]CXCL12 (SDF-1α)Regulation of chemokine
n2:mentions
n3:12135369
Subject Item
_:vb94664105
rdf:type
n2:Context
rdf:value
anti-inflammatory response[68]E-cadherinJunction protein degradation[36]MMP-7MatrilysinSyndecan-1 (CXCL1 release)Chemotactic gradient[56]proTNFαTNF-α activation[65]MMP-8Collagenase-2LIXChemotactic gradient[>>52<<]CXCL6, CXCL5, LIXRegulation of chemokine signaling[54]OccludinJunction protein degradation[131]MMP-9Gelatinase BCXCL8 (IL-8)Chemotactic gradient[46]CXCL12 (SDF-1α)Regulation of chemokine signaling[49]CXCL6, CXCL5, LIX[54](CCL11, CCL7,
n2:mentions
n3:17375198
Subject Item
_:vb94664106
rdf:type
n2:Context
rdf:value
protein degradation[36]MMP-7MatrilysinSyndecan-1 (CXCL1 release)Chemotactic gradient[56]proTNFαTNF-α activation[65]MMP-8Collagenase-2LIXChemotactic gradient[52]CXCL6, CXCL5, LIXRegulation of chemokine signaling[>>54<<]OccludinJunction protein degradation[131]MMP-9Gelatinase BCXCL8 (IL-8)Chemotactic gradient[46]CXCL12 (SDF-1α)Regulation of chemokine signaling[49]CXCL6, CXCL5, LIX[54](CCL11, CCL7, CCL17 gradient)[58]pIL-1βIL-1β activation[62]Latent
n2:mentions
n3:12950257
Subject Item
_:vb94664107
rdf:type
n2:Context
rdf:value
(CXCL1 release)Chemotactic gradient[56]proTNFαTNF-α activation[65]MMP-8Collagenase-2LIXChemotactic gradient[52]CXCL6, CXCL5, LIXRegulation of chemokine signaling[54]OccludinJunction protein degradation[>>131<<]MMP-9Gelatinase BCXCL8 (IL-8)Chemotactic gradient[46]CXCL12 (SDF-1α)Regulation of chemokine signaling[49]CXCL6, CXCL5, LIX[54](CCL11, CCL7, CCL17 gradient)[58]pIL-1βIL-1β activation[62]Latent TGF-β1Pot.
n2:mentions
n3:20442866
Subject Item
_:vb94664108
rdf:type
n2:Context
rdf:value
gradient[56]proTNFαTNF-α activation[65]MMP-8Collagenase-2LIXChemotactic gradient[52]CXCL6, CXCL5, LIXRegulation of chemokine signaling[54]OccludinJunction protein degradation[131]MMP-9Gelatinase BCXCL8 (IL-8)Chemotactic gradient[>>46<<]CXCL12 (SDF-1α)Regulation of chemokine signaling[49]CXCL6, CXCL5, LIX[54](CCL11, CCL7, CCL17 gradient)[58]pIL-1βIL-1β activation[62]Latent TGF-β1Pot.
n2:mentions
n3:11023497
Subject Item
_:vb94664109
rdf:type
n2:Context
rdf:value
gradient[52]CXCL6, CXCL5, LIXRegulation of chemokine signaling[54]OccludinJunction protein degradation[131]MMP-9Gelatinase BCXCL8 (IL-8)Chemotactic gradient[46]CXCL12 (SDF-1α)Regulation of chemokine signaling[>>49<<]CXCL6, CXCL5, LIX[54](CCL11, CCL7, CCL17 gradient)[58]pIL-1βIL-1β activation[62]Latent TGF-β1Pot.
n2:mentions
n3:11571304
Subject Item
_:vb94664110
rdf:type
n2:Context
rdf:value
gradient[52]CXCL6, CXCL5, LIXRegulation of chemokine signaling[54]OccludinJunction protein degradation[131]MMP-9Gelatinase BCXCL8 (IL-8)Chemotactic gradient[46]CXCL12 (SDF-1α)Regulation of chemokine signaling[49]CXCL6, CXCL5, LIX[>>54<<](CCL11, CCL7, CCL17 gradient)[58]pIL-1βIL-1β activation[62]Latent TGF-β1Pot.
n2:mentions
n3:12950257
Subject Item
_:vb94664111
rdf:type
n2:Context
rdf:value
LIXRegulation of chemokine signaling[54]OccludinJunction protein degradation[131]MMP-9Gelatinase BCXCL8 (IL-8)Chemotactic gradient[46]CXCL12 (SDF-1α)Regulation of chemokine signaling[49]CXCL6, CXCL5, LIX[54](CCL11, CCL7, CCL17 gradient)[>>58<<]pIL-1βIL-1β activation[62]Latent TGF-β1Pot.
n2:mentions
n3:15059974
Subject Item
_:vb94664112
rdf:type
n2:Context
rdf:value
signaling[54]OccludinJunction protein degradation[131]MMP-9Gelatinase BCXCL8 (IL-8)Chemotactic gradient[46]CXCL12 (SDF-1α)Regulation of chemokine signaling[49]CXCL6, CXCL5, LIX[54](CCL11, CCL7, CCL17 gradient)[58]pIL-1βIL-1β activation[>>62<<]Latent TGF-β1Pot.
n2:mentions
n3:9759850
Subject Item
_:vb94664113
rdf:type
n2:Context
rdf:value
anti-inflammatory response[>>66<<]Claudin-5, occludin, ZO-1Junction protein degradation[25–27]MMP-13Collagenase-3CCL7Regulation of chemokine signaling[48]CXCL12 (SDF-1α)[49]MMP-14MT1-MMPCCL7Regulation of chemokine signaling[48]CXCL12 (SDF-1α)[49]Latent TGF-β1Pot.
n2:mentions
n3:10652271
Subject Item
_:vb94664114
rdf:type
n2:Context
rdf:value
anti-inflammatory response[66]Claudin-5, occludin, ZO-1Junction protein degradation[>>25<<–27]MMP-13Collagenase-3CCL7Regulation of chemokine signaling[48]CXCL12 (SDF-1α)[49]MMP-14MT1-MMPCCL7Regulation of chemokine signaling[48]CXCL12 (SDF-1α)[49]Latent TGF-β1Pot.
n2:mentions
n3:18799677 n3:19821483 n3:16850029
Subject Item
_:vb94664115
rdf:type
n2:Context
rdf:value
anti-inflammatory response[66]Claudin-5, occludin, ZO-1Junction protein degradation[25–27]MMP-13Collagenase-3CCL7Regulation of chemokine signaling[>>48<<]CXCL12 (SDF-1α)[49]MMP-14MT1-MMPCCL7Regulation of chemokine signaling[48]CXCL12 (SDF-1α)[49]Latent TGF-β1Pot.
n2:mentions
n3:12149192
Subject Item
_:vb94664116
rdf:type
n2:Context
rdf:value
anti-inflammatory response[66]Claudin-5, occludin, ZO-1Junction protein degradation[25–27]MMP-13Collagenase-3CCL7Regulation of chemokine signaling[48]CXCL12 (SDF-1α)[>>49<<]MMP-14MT1-MMPCCL7Regulation of chemokine signaling[48]CXCL12 (SDF-1α)[49]Latent TGF-β1Pot.
n2:mentions
n3:11571304
Subject Item
_:vb94664117
rdf:type
n2:Context
rdf:value
anti-inflammatory response[66]Claudin-5, occludin, ZO-1Junction protein degradation[25–27]MMP-13Collagenase-3CCL7Regulation of chemokine signaling[48]CXCL12 (SDF-1α)[49]MMP-14MT1-MMPCCL7Regulation of chemokine signaling[>>48<<]CXCL12 (SDF-1α)[49]Latent TGF-β1Pot.
n2:mentions
n3:12149192
Subject Item
_:vb94664118
rdf:type
n2:Context
rdf:value
response[66]Claudin-5, occludin, ZO-1Junction protein degradation[25–27]MMP-13Collagenase-3CCL7Regulation of chemokine signaling[48]CXCL12 (SDF-1α)[49]MMP-14MT1-MMPCCL7Regulation of chemokine signaling[48]CXCL12 (SDF-1α)[>>49<<]Latent TGF-β1Pot.
n2:mentions
n3:11571304
Subject Item
_:vb94664119
rdf:type
n2:Context
rdf:value
anti-inflammatory response[>>67<<]ADAM-10CD156cIL-6RIL-6 trans-signaling[77, 78]EGF, betacellulinEGFR signaling[82]VE-cadherinJunction protein degradation[43, 44]ADAM-17TACEproTNF-αTNF-α activation[63, 64]TNFR1, TNFR2TNFR shedding, TNF-α antagonization[73, 74]IL-6RIL-6
n2:mentions
n3:12226090
Subject Item
_:vb94664120
rdf:type
n2:Context
rdf:value
anti-inflammatory response[67]ADAM-10CD156cIL-6RIL-6 trans-signaling[>>77<<, 78]EGF, betacellulinEGFR signaling[82]VE-cadherinJunction protein degradation[43, 44]ADAM-17TACEproTNF-αTNF-α activation[63, 64]TNFR1, TNFR2TNFR shedding, TNF-α antagonization[73, 74]IL-6RIL-6 trans-signaling[77, 78]EPR, TGF-α, AREG,
n2:mentions
n3:21454673
Subject Item
_:vb94664121
rdf:type
n2:Context
rdf:value
anti-inflammatory response[67]ADAM-10CD156cIL-6RIL-6 trans-signaling[77, >>78<<]EGF, betacellulinEGFR signaling[82]VE-cadherinJunction protein degradation[43, 44]ADAM-17TACEproTNF-αTNF-α activation[63, 64]TNFR1, TNFR2TNFR shedding, TNF-α antagonization[73, 74]IL-6RIL-6 trans-signaling[77, 78]EPR, TGF-α, AREG,
n2:mentions
n3:18490707
Subject Item
_:vb94664122
rdf:type
n2:Context
rdf:value
anti-inflammatory response[67]ADAM-10CD156cIL-6RIL-6 trans-signaling[77, 78]EGF, betacellulinEGFR signaling[>>82<<]VE-cadherinJunction protein degradation[43, 44]ADAM-17TACEproTNF-αTNF-α activation[63, 64]TNFR1, TNFR2TNFR shedding, TNF-α antagonization[73, 74]IL-6RIL-6 trans-signaling[77, 78]EPR, TGF-α, AREG, HB-EGFEGFR
n2:mentions
n3:14993236
Subject Item
_:vb94664123
rdf:type
n2:Context
rdf:value
anti-inflammatory response[67]ADAM-10CD156cIL-6RIL-6 trans-signaling[77, 78]EGF, betacellulinEGFR signaling[82]VE-cadherinJunction protein degradation[>>43<<, 44]ADAM-17TACEproTNF-αTNF-α activation[63, 64]TNFR1, TNFR2TNFR shedding, TNF-α antagonization[73, 74]IL-6RIL-6 trans-signaling[77, 78]EPR, TGF-α, AREG, HB-EGFEGFR signaling[82]L-selectinLeukocyte migration[80]Fig.
n2:mentions
n3:21926978
Subject Item
_:vb94664124
rdf:type
n2:Context
rdf:value
anti-inflammatory response[67]ADAM-10CD156cIL-6RIL-6 trans-signaling[77, 78]EGF, betacellulinEGFR signaling[82]VE-cadherinJunction protein degradation[43, >>44<<]ADAM-17TACEproTNF-αTNF-α activation[63, 64]TNFR1, TNFR2TNFR shedding, TNF-α antagonization[73, 74]IL-6RIL-6 trans-signaling[77, 78]EPR, TGF-α, AREG, HB-EGFEGFR signaling[82]L-selectinLeukocyte migration[80]Fig.
n2:mentions
n3:18497310
Subject Item
_:vb94664125
rdf:type
n2:Context
rdf:value
anti-inflammatory response[67]ADAM-10CD156cIL-6RIL-6 trans-signaling[77, 78]EGF, betacellulinEGFR signaling[82]VE-cadherinJunction protein degradation[43, 44]ADAM-17TACEproTNF-αTNF-α activation[>>63<<, 64]TNFR1, TNFR2TNFR shedding, TNF-α antagonization[73, 74]IL-6RIL-6 trans-signaling[77, 78]EPR, TGF-α, AREG, HB-EGFEGFR signaling[82]L-selectinLeukocyte migration[80]Fig.
n2:mentions
n3:9034191
Subject Item
_:vb94664126
rdf:type
n2:Context
rdf:value
anti-inflammatory response[67]ADAM-10CD156cIL-6RIL-6 trans-signaling[77, 78]EGF, betacellulinEGFR signaling[82]VE-cadherinJunction protein degradation[43, 44]ADAM-17TACEproTNF-αTNF-α activation[63, >>64<<]TNFR1, TNFR2TNFR shedding, TNF-α antagonization[73, 74]IL-6RIL-6 trans-signaling[77, 78]EPR, TGF-α, AREG, HB-EGFEGFR signaling[82]L-selectinLeukocyte migration[80]Fig.
n2:mentions
n3:9034190
Subject Item
_:vb94664127
rdf:type
n2:Context
rdf:value
response[67]ADAM-10CD156cIL-6RIL-6 trans-signaling[77, 78]EGF, betacellulinEGFR signaling[82]VE-cadherinJunction protein degradation[43, 44]ADAM-17TACEproTNF-αTNF-α activation[63, 64]TNFR1, TNFR2TNFR shedding, TNF-α antagonization[>>73<<, 74]IL-6RIL-6 trans-signaling[77, 78]EPR, TGF-α, AREG, HB-EGFEGFR signaling[82]L-selectinLeukocyte migration[80]Fig.
n2:mentions
n3:17510296
Subject Item
_:vb94664128
rdf:type
n2:Context
rdf:value
response[67]ADAM-10CD156cIL-6RIL-6 trans-signaling[77, 78]EGF, betacellulinEGFR signaling[82]VE-cadherinJunction protein degradation[43, 44]ADAM-17TACEproTNF-αTNF-α activation[63, 64]TNFR1, TNFR2TNFR shedding, TNF-α antagonization[73, >>74<<]IL-6RIL-6 trans-signaling[77, 78]EPR, TGF-α, AREG, HB-EGFEGFR signaling[82]L-selectinLeukocyte migration[80]Fig.
n2:mentions
n3:9812885
Subject Item
_:vb94664129
rdf:type
n2:Context
rdf:value
trans-signaling[77, 78]EGF, betacellulinEGFR signaling[82]VE-cadherinJunction protein degradation[43, 44]ADAM-17TACEproTNF-αTNF-α activation[63, 64]TNFR1, TNFR2TNFR shedding, TNF-α antagonization[73, 74]IL-6RIL-6 trans-signaling[>>77<<, 78]EPR, TGF-α, AREG, HB-EGFEGFR signaling[82]L-selectinLeukocyte migration[80]Fig.
n2:mentions
n3:21454673
Subject Item
_:vb94664130
rdf:type
n2:Context
rdf:value
trans-signaling[77, 78]EGF, betacellulinEGFR signaling[82]VE-cadherinJunction protein degradation[43, 44]ADAM-17TACEproTNF-αTNF-α activation[63, 64]TNFR1, TNFR2TNFR shedding, TNF-α antagonization[73, 74]IL-6RIL-6 trans-signaling[77, >>78<<]EPR, TGF-α, AREG, HB-EGFEGFR signaling[82]L-selectinLeukocyte migration[80]Fig.
n2:mentions
n3:18490707
Subject Item
_:vb94664131
rdf:type
n2:Context
rdf:value
signaling[82]VE-cadherinJunction protein degradation[43, 44]ADAM-17TACEproTNF-αTNF-α activation[63, 64]TNFR1, TNFR2TNFR shedding, TNF-α antagonization[73, 74]IL-6RIL-6 trans-signaling[77, 78]EPR, TGF-α, AREG, HB-EGFEGFR signaling[>>82<<]L-selectinLeukocyte migration[80]Fig.
n2:mentions
n3:14993236
Subject Item
_:vb94664132
rdf:type
n2:Context
rdf:value
protein degradation[43, 44]ADAM-17TACEproTNF-αTNF-α activation[63, 64]TNFR1, TNFR2TNFR shedding, TNF-α antagonization[73, 74]IL-6RIL-6 trans-signaling[77, 78]EPR, TGF-α, AREG, HB-EGFEGFR signaling[82]L-selectinLeukocyte migration[>>80<<]Fig.
n2:mentions
n3:21628404
Subject Item
_:vb94664133
rdf:type
n2:Context
rdf:value
For simplicity, the BBB is depicted without pericytes and astrocytes. Illustration design inspired by Khokha et al. [>>15<<
n2:mentions
n3:23969736
Subject Item
_:vb94664134
rdf:type
n2:Context
rdf:value
Metalloproteinases have been demonstrated to be involved in these processes not only by degrading ECM and promoting effector cell extravasation but also by regulation of chemotactic gradients [>>15<<]. This was first demonstrated with MMP-9 shown to process an amino-terminal fragment of IL-8, thereby increasing its chemoattractant properties to more efficiently recruit neutrophils [46]. On the other hand, MMP-2 was shown to inactivate
n2:mentions
n3:23969736
Subject Item
_:vb94664135
rdf:type
n2:Context
rdf:value
This was first demonstrated with MMP-9 shown to process an amino-terminal fragment of IL-8, thereby increasing its chemoattractant properties to more efficiently recruit neutrophils [>>46<<]. On the other hand, MMP-2 was shown to inactivate monocyte chemotactic protein 3 (MCP3, also known as chemokine (C–C motif) ligand 7, CCL7) by removing an amino-terminal tetrapeptide, converting it to an antagonist of its chemokine
n2:mentions
n3:11023497
Subject Item
_:vb94664136
rdf:type
n2:Context
rdf:value
other hand, MMP-2 was shown to inactivate monocyte chemotactic protein 3 (MCP3, also known as chemokine (C–C motif) ligand 7, CCL7) by removing an amino-terminal tetrapeptide, converting it to an antagonist of its chemokine receptors [>>47<<]. Conceptually, these findings showed that MMPs can not only act as effectors but also regulators of inflammatory responses [47].
n2:mentions
n3:10947989
Subject Item
_:vb94664137
rdf:type
n2:Context
rdf:value
Conceptually, these findings showed that MMPs can not only act as effectors but also regulators of inflammatory responses [>>47<<]. Subsequently, CCL7 has been also shown to be a specific substrate of MMP-1, -3, -13 and -14 but not MMP-8 and -9 [48]. The closely related chemokines CCL2, CCL8 and CCL13 (MCP-1, -2 and -4) are proteolytically cleaved by MMP-1 and -3
n2:mentions
n3:10947989
Subject Item
_:vb94664138
rdf:type
n2:Context
rdf:value
Subsequently, CCL7 has been also shown to be a specific substrate of MMP-1, -3, -13 and -14 but not MMP-8 and -9 [>>48<<]. The closely related chemokines CCL2, CCL8 and CCL13 (MCP-1, -2 and -4) are proteolytically cleaved by MMP-1 and -3 (but not MMP-2 and -14) with the truncated products of CCL8 and CCL13 being potent antagonists of the their respective
n2:mentions
n3:12149192
Subject Item
_:vb94664139
rdf:type
n2:Context
rdf:value
chemokines CCL2, CCL8 and CCL13 (MCP-1, -2 and -4) are proteolytically cleaved by MMP-1 and -3 (but not MMP-2 and -14) with the truncated products of CCL8 and CCL13 being potent antagonists of the their respective chemokine receptors [>>48<<]. Apart from influencing the activity of C–C motif chemokines, MMPs also contribute to CXC-chemokine function.
n2:mentions
n3:12149192
Subject Item
_:vb94664140
rdf:type
n2:Context
rdf:value
Stromal cell-derived factor 1 alpha (SDF-1α, also known as CXCL12) is processed and inactivated by MMP-1, -2, -3, -9, -13 and -14 but not by MMP-7 and -8 [>>49<<]. The truncated form of CXCL12 after MMP-2 processing demonstrates highly neurotoxic properties [50]. An elegant study with single and double knockout mice for MMP-2 and MMP-9 revealed that these MMPs work synergistically in the initial
n2:mentions
n3:11571304
Subject Item
_:vb94664141
rdf:type
n2:Context
rdf:value
The truncated form of CXCL12 after MMP-2 processing demonstrates highly neurotoxic properties [>>50<<]. An elegant study with single and double knockout mice for MMP-2 and MMP-9 revealed that these MMPs work synergistically in the initial step of neutrophil recruitment to injury sites by increasing the potency of CXC-chemokine ligand 5
n2:mentions
n3:14502291
Subject Item
_:vb94664142
rdf:type
n2:Context
rdf:value
study with single and double knockout mice for MMP-2 and MMP-9 revealed that these MMPs work synergistically in the initial step of neutrophil recruitment to injury sites by increasing the potency of CXC-chemokine ligand 5 (CXCL5) [>>51<<]. Activation of murine LPS-induced CXC chemokine (LIX, similar to the human neutrophil-recruiting chemokine CXCL5 and CXCL8/IL-8) is dependent on MMP-8, with cleaved LIX promoting enhanced chemotaxis [52].
n2:mentions
n3:23225890
Subject Item
_:vb94664143
rdf:type
n2:Context
rdf:value
Activation of murine LPS-induced CXC chemokine (LIX, similar to the human neutrophil-recruiting chemokine CXCL5 and CXCL8/IL-8) is dependent on MMP-8, with cleaved LIX promoting enhanced chemotaxis [>>52<<]. Neutrophil infiltration at LPS-stimulated sites is clearly diminished in mmp8−/− mice [52]. The same study showed that MMP-8 itself is not required for the extravasation and migration of neutrophils, but plays a very crucial role in
n2:mentions
n3:17375198
Subject Item
_:vb94664144
rdf:type
n2:Context
rdf:value
Neutrophil infiltration at LPS-stimulated sites is clearly diminished in mmp8−/− mice [>>52<<]. The same study showed that MMP-8 itself is not required for the extravasation and migration of neutrophils, but plays a very crucial role in orchestrating the initial inflammatory response upon LPS stimulation, thereby indicating that
n2:mentions
n3:17375198
Subject Item
_:vb94664145
rdf:type
n2:Context
rdf:value
and migration of neutrophils, but plays a very crucial role in orchestrating the initial inflammatory response upon LPS stimulation, thereby indicating that chemoattractants rather than collagen are MMP-8’s primary substrates [>>52<<]. Nevertheless, collagens processed by MMP-8 can also act as chemotactic peptides during neutrophil chemotaxis [53].
n2:mentions
n3:17375198
Subject Item
_:vb94664146
rdf:type
n2:Context
rdf:value
Nevertheless, collagens processed by MMP-8 can also act as chemotactic peptides during neutrophil chemotaxis [>>53<<]. Both MMP-8 and -9 are reported to cleave CXCL5 and CXCL6, but no change in biological activity of CXCL6 was demonstrated [54]. MMP-9, in contrast, potently inactivates CXCL5 by multiple cleavages, suggesting a regulatory role of MMP-9
n2:mentions
n3:23233663
Subject Item
_:vb94664147
rdf:type
n2:Context
rdf:value
Both MMP-8 and -9 are reported to cleave CXCL5 and CXCL6, but no change in biological activity of CXCL6 was demonstrated [>>54<<]. MMP-9, in contrast, potently inactivates CXCL5 by multiple cleavages, suggesting a regulatory role of MMP-9 in early activation with subsequent inactivation of CXCL5 [54]. In addition to direct effects of MMPs on chemokines, MMPs might
n2:mentions
n3:12950257
Subject Item
_:vb94664148
rdf:type
n2:Context
rdf:value
MMP-9, in contrast, potently inactivates CXCL5 by multiple cleavages, suggesting a regulatory role of MMP-9 in early activation with subsequent inactivation of CXCL5 [>>54<<]. In addition to direct effects of MMPs on chemokines, MMPs might also regulate the expression of chemokine receptors, thereby providing an additional level by which these proteinases control leukocyte migration [5, 55].
n2:mentions
n3:12950257
Subject Item
_:vb94664149
rdf:type
n2:Context
rdf:value
In addition to direct effects of MMPs on chemokines, MMPs might also regulate the expression of chemokine receptors, thereby providing an additional level by which these proteinases control leukocyte migration [>>5<<, 55].
n2:mentions
n3:15286728
Subject Item
_:vb94664150
rdf:type
n2:Context
rdf:value
In addition to direct effects of MMPs on chemokines, MMPs might also regulate the expression of chemokine receptors, thereby providing an additional level by which these proteinases control leukocyte migration [5, >>55<<].
n2:mentions
n3:10090924
Subject Item
_:vb94664151
rdf:type
n2:Context
rdf:value
Besides directly processing chemokines and altering their biological function, MMPs can also indirectly influence the availability and activity of chemokines by cleaving accessory macromolecules that bind them [>>56<<]. Thereby, MMPs exhibit an additional way of regulating leukocyte migration [5].
n2:mentions
n3:12464176
Subject Item
_:vb94664152
rdf:type
n2:Context
rdf:value
Thereby, MMPs exhibit an additional way of regulating leukocyte migration [>>5<<]. MMP-7 is involved in syndecan-1 cleavage, which in turn releases CXCL1 (also known as KC).
n2:mentions
n3:15286728
Subject Item
_:vb94664153
rdf:type
n2:Context
rdf:value
Thereby, MMP-7 indirectly generates a chemotactic gradient that directs neutrophil migration to sites of injury [>>56<<]. Consequently, neutrophil infiltration is massively reduced in mmp7−/− mice at sites of injury because of impaired transepithelial migration [56]. Other MMPs also regulate chemotactic gradients, but their role is less well understood.
n2:mentions
n3:12464176
Subject Item
_:vb94664154
rdf:type
n2:Context
rdf:value
Consequently, neutrophil infiltration is massively reduced in mmp7−/− mice at sites of injury because of impaired transepithelial migration [>>56<<]. Other MMPs also regulate chemotactic gradients, but their role is less well understood. MMP-2 seems to be critical for establishing a CCL11 (eotaxin) chemotactic gradient during leukocyte recruitment, as allergen-induced asthmatic
n2:mentions
n3:12464176
Subject Item
_:vb94664155
rdf:type
n2:Context
rdf:value
MMP-2 seems to be critical for establishing a CCL11 (eotaxin) chemotactic gradient during leukocyte recruitment, as allergen-induced asthmatic mmp2−/− mice show leukocyte accumulation in lung parenchyma and decreased CCL11 levels [>>57<<]. Notably, this indirect pro-inflammatory effect of MMP-2 is very distinct from the above discussed direct anti-inflammatory function via chemokine cleavage and inactivation [47, 49].
n2:mentions
n3:11887181
Subject Item
_:vb94664156
rdf:type
n2:Context
rdf:value
Notably, this indirect pro-inflammatory effect of MMP-2 is very distinct from the above discussed direct anti-inflammatory function via chemokine cleavage and inactivation [>>47<<, 49]. In addition to MMP-2, MMP-9 contributes to the generation of the chemotactic gradient in allergen-induced asthmatic mice, where mmp9−/− mice showed diminished CCL11, CCL7 and CCL17 chemoattractant levels [58]. In summary, these
n2:mentions
n3:10947989
Subject Item
_:vb94664157
rdf:type
n2:Context
rdf:value
Notably, this indirect pro-inflammatory effect of MMP-2 is very distinct from the above discussed direct anti-inflammatory function via chemokine cleavage and inactivation [47, >>49<<]. In addition to MMP-2, MMP-9 contributes to the generation of the chemotactic gradient in allergen-induced asthmatic mice, where mmp9−/− mice showed diminished CCL11, CCL7 and CCL17 chemoattractant levels [58]. In summary, these studies
n2:mentions
n3:11571304
Subject Item
_:vb94664158
rdf:type
n2:Context
rdf:value
In addition to MMP-2, MMP-9 contributes to the generation of the chemotactic gradient in allergen-induced asthmatic mice, where mmp9−/− mice showed diminished CCL11, CCL7 and CCL17 chemoattractant levels [>>58<<]. In summary, these studies demonstrate that MMPs are important regulators of inflammation by controlling chemokine activity and chemotactic gradients, thereby manipulating leukocyte migration.
n2:mentions
n3:15059974
Subject Item
_:vb94664159
rdf:type
n2:Context
rdf:value
The pro-inflammatory cytokine IL-1β needs proteolytic activation by the IL-1β-converting enzyme (ICE, more recently re-named to caspase-1) [>>59<<, 60]. After discovery of caspase-1-independent activation of IL-1β [61], MMP-2, -3 and -9 were described to process human IL-1β precursor into biologically active forms [62]. In addition, MMP-3—to a lesser extent MMP-9, but not
n2:mentions
n3:1574116
Subject Item
_:vb94664160
rdf:type
n2:Context
rdf:value
The pro-inflammatory cytokine IL-1β needs proteolytic activation by the IL-1β-converting enzyme (ICE, more recently re-named to caspase-1) [59, >>60<<]. After discovery of caspase-1-independent activation of IL-1β [61], MMP-2, -3 and -9 were described to process human IL-1β precursor into biologically active forms [62]. In addition, MMP-3—to a lesser extent MMP-9, but not
n2:mentions
n3:2787508
Subject Item
_:vb94664161
rdf:type
n2:Context
rdf:value
After discovery of caspase-1-independent activation of IL-1β [>>61<<], MMP-2, -3 and -9 were described to process human IL-1β precursor into biologically active forms [62].
n2:mentions
n3:9029121
Subject Item
_:vb94664162
rdf:type
n2:Context
rdf:value
After discovery of caspase-1-independent activation of IL-1β [61], MMP-2, -3 and -9 were described to process human IL-1β precursor into biologically active forms [>>62<<]. In addition, MMP-3—to a lesser extent MMP-9, but not collagenases—was found to degrade active IL-1β after longer incubation periods, indicating regulatory roles of MMPs in both IL-1β activation and inactivation [62]. Under physiological
n2:mentions
n3:9759850
Subject Item
_:vb94664163
rdf:type
n2:Context
rdf:value
In addition, MMP-3—to a lesser extent MMP-9, but not collagenases—was found to degrade active IL-1β after longer incubation periods, indicating regulatory roles of MMPs in both IL-1β activation and inactivation [>>62<<]. Under physiological conditions, conversion of the membrane-bound pro-TNF-α to its active and soluble form is attributed to TNF-α-converting enzyme (TACE, now known as ADAM17, also see next section) [63, 64]. Even if ADAM17 is the most
n2:mentions
n3:9759850
Subject Item
_:vb94664164
rdf:type
n2:Context
rdf:value
Under physiological conditions, conversion of the membrane-bound pro-TNF-α to its active and soluble form is attributed to TNF-α-converting enzyme (TACE, now known as ADAM17, also see next section) [>>63<<, 64]. Even if ADAM17 is the most specific and best convertor of pro-TNF-α, MMP-7—and to lesser but not physiologically relevant extent MMP-1 and -9—harbors the capacity to cleave and activate pro-TNF-α and seems to act as another
n2:mentions
n3:9034191
Subject Item
_:vb94664165
rdf:type
n2:Context
rdf:value
Under physiological conditions, conversion of the membrane-bound pro-TNF-α to its active and soluble form is attributed to TNF-α-converting enzyme (TACE, now known as ADAM17, also see next section) [63, >>64<<]. Even if ADAM17 is the most specific and best convertor of pro-TNF-α, MMP-7—and to lesser but not physiologically relevant extent MMP-1 and -9—harbors the capacity to cleave and activate pro-TNF-α and seems to act as another
n2:mentions
n3:9034190
Subject Item
_:vb94664166
rdf:type
n2:Context
rdf:value
the most specific and best convertor of pro-TNF-α, MMP-7—and to lesser but not physiologically relevant extent MMP-1 and -9—harbors the capacity to cleave and activate pro-TNF-α and seems to act as another physiological TNF-α convertor [>>65<<]. In contrast to the activation of these pro-inflammatory cytokines, MMPs (MMP-3, -9 and -14) are also able to activate transforming growth factor-β1 (TGF-β1) in vitro [66–68], which restrains mononuclear inflammation [5, 69, 70], thereby
n2:mentions
n3:12135369
Subject Item
_:vb94664167
rdf:type
n2:Context
rdf:value
In contrast to the activation of these pro-inflammatory cytokines, MMPs (MMP-3, -9 and -14) are also able to activate transforming growth factor-β1 (TGF-β1) in vitro [>>66<<–68], which restrains mononuclear inflammation [5, 69, 70], thereby again indicating an overall regulatory effect of MMPs in inflammation.
n2:mentions
n3:12226090 n3:10652271 n3:11907708
Subject Item
_:vb94664168
rdf:type
n2:Context
rdf:value
In contrast to the activation of these pro-inflammatory cytokines, MMPs (MMP-3, -9 and -14) are also able to activate transforming growth factor-β1 (TGF-β1) in vitro [66–68], which restrains mononuclear inflammation [>>5<<, 69, 70], thereby again indicating an overall regulatory effect of MMPs in inflammation.
n2:mentions
n3:15286728
Subject Item
_:vb94664169
rdf:type
n2:Context
rdf:value
In contrast to the activation of these pro-inflammatory cytokines, MMPs (MMP-3, -9 and -14) are also able to activate transforming growth factor-β1 (TGF-β1) in vitro [66–68], which restrains mononuclear inflammation [5, >>69<<, 70], thereby again indicating an overall regulatory effect of MMPs in inflammation.
n2:mentions
n3:10025398
Subject Item
_:vb94664170
rdf:type
n2:Context
rdf:value
In contrast to the activation of these pro-inflammatory cytokines, MMPs (MMP-3, -9 and -14) are also able to activate transforming growth factor-β1 (TGF-β1) in vitro [66–68], which restrains mononuclear inflammation [5, 69, >>70<<], thereby again indicating an overall regulatory effect of MMPs in inflammation.
n2:mentions
n3:1436033
Subject Item
_:vb94664171
rdf:type
n2:Context
rdf:value
TNF-α-converting enzyme (TACE; ADAM17) was originally thought to be a MMP, as it was effectively inhibited by synthetic metalloproteinase inhibitors [>>71<<], but later found to belong the ADAM family and identified as ADAM17 [63, 64].
n2:mentions
n3:8052310
Subject Item
_:vb94664172
rdf:type
n2:Context
rdf:value
TNF-α-converting enzyme (TACE; ADAM17) was originally thought to be a MMP, as it was effectively inhibited by synthetic metalloproteinase inhibitors [71], but later found to belong the ADAM family and identified as ADAM17 [>>63<<, 64]. ADAM17 shows very distinct specificity for shedding membrane-bound pro-TNF-α, thereby releasing biologically active TNF-α [65], with both pro-inflammatory and pro-apoptotic functions [15].
n2:mentions
n3:9034191
Subject Item
_:vb94664173
rdf:type
n2:Context
rdf:value
TNF-α-converting enzyme (TACE; ADAM17) was originally thought to be a MMP, as it was effectively inhibited by synthetic metalloproteinase inhibitors [71], but later found to belong the ADAM family and identified as ADAM17 [63, >>64<<]. ADAM17 shows very distinct specificity for shedding membrane-bound pro-TNF-α, thereby releasing biologically active TNF-α [65], with both pro-inflammatory and pro-apoptotic functions [15].
n2:mentions
n3:9034190
Subject Item
_:vb94664174
rdf:type
n2:Context
rdf:value
ADAM17 shows very distinct specificity for shedding membrane-bound pro-TNF-α, thereby releasing biologically active TNF-α [>>65<<], with both pro-inflammatory and pro-apoptotic functions [15].
n2:mentions
n3:12135369
Subject Item
_:vb94664175
rdf:type
n2:Context
rdf:value
ADAM17 shows very distinct specificity for shedding membrane-bound pro-TNF-α, thereby releasing biologically active TNF-α [65], with both pro-inflammatory and pro-apoptotic functions [>>15<<]. In ADAM17-deficient cells, TNF-α release is reduced by 90%, indicating that ADAM17 is the principal TNF-α converting enzyme [5, 64]. Soluble TNF-α signals via binding of TNF receptor 1 (TNFR1), whereas membrane-bound TNF-α acts
n2:mentions
n3:23969736
Subject Item
_:vb94664176
rdf:type
n2:Context
rdf:value
In ADAM17-deficient cells, TNF-α release is reduced by 90%, indicating that ADAM17 is the principal TNF-α converting enzyme [>>5<<, 64]. Soluble TNF-α signals via binding of TNF receptor 1 (TNFR1), whereas membrane-bound TNF-α acts preferentially through binding of TNFR2 [72]. The regulation of TNF signaling by ADAM17 is even more complex, since ADAM17 also sheds
n2:mentions
n3:15286728
Subject Item
_:vb94664177
rdf:type
n2:Context
rdf:value
In ADAM17-deficient cells, TNF-α release is reduced by 90%, indicating that ADAM17 is the principal TNF-α converting enzyme [5, >>64<<]. Soluble TNF-α signals via binding of TNF receptor 1 (TNFR1), whereas membrane-bound TNF-α acts preferentially through binding of TNFR2 [72]. The regulation of TNF signaling by ADAM17 is even more complex, since ADAM17 also sheds TNFR1
n2:mentions
n3:9034190
Subject Item
_:vb94664178
rdf:type
n2:Context
rdf:value
Soluble TNF-α signals via binding of TNF receptor 1 (TNFR1), whereas membrane-bound TNF-α acts preferentially through binding of TNFR2 [>>72<<]. The regulation of TNF signaling by ADAM17 is even more complex, since ADAM17 also sheds TNFR1 and TNFR2 [73, 74]. These act as decoy receptors by sequestering soluble TNF-α away from their receptors [15]. ADAM17 deficiency in myeloid
n2:mentions
n3:8521496
Subject Item
_:vb94664179
rdf:type
n2:Context
rdf:value
The regulation of TNF signaling by ADAM17 is even more complex, since ADAM17 also sheds TNFR1 and TNFR2 [>>73<<, 74]. These act as decoy receptors by sequestering soluble TNF-α away from their receptors [15]. ADAM17 deficiency in myeloid cells protected mice from endotoxin-induced septic shock by preventing increased serum levels of TNF-α [75]. As
n2:mentions
n3:17510296
Subject Item
_:vb94664180
rdf:type
n2:Context
rdf:value
The regulation of TNF signaling by ADAM17 is even more complex, since ADAM17 also sheds TNFR1 and TNFR2 [73, >>74<<]. These act as decoy receptors by sequestering soluble TNF-α away from their receptors [15]. ADAM17 deficiency in myeloid cells protected mice from endotoxin-induced septic shock by preventing increased serum levels of TNF-α [75]. As
n2:mentions
n3:9812885
Subject Item
_:vb94664181
rdf:type
n2:Context
rdf:value
These act as decoy receptors by sequestering soluble TNF-α away from their receptors [>>15<<]. ADAM17 deficiency in myeloid cells protected mice from endotoxin-induced septic shock by preventing increased serum levels of TNF-α [75]. As ADAM17-dependent TNF-α conversion is selectively inhibited by TIMP3 [14], Timp3−/− mice show
n2:mentions
n3:23969736
Subject Item
_:vb94664182
rdf:type
n2:Context
rdf:value
ADAM17 deficiency in myeloid cells protected mice from endotoxin-induced septic shock by preventing increased serum levels of TNF-α [>>75<<]. As ADAM17-dependent TNF-α conversion is selectively inhibited by TIMP3 [14], Timp3−/− mice show enhanced TNF-α signaling with elevated IL-6 serum levels and increased mortality after LPS-induced sepsis [76]. ADAM17—but also ADAM10—have
n2:mentions
n3:17709479
Subject Item
_:vb94664183
rdf:type
n2:Context
rdf:value
As ADAM17-dependent TNF-α conversion is selectively inhibited by TIMP3 [14], Timp3−/− mice show enhanced TNF-α signaling with elevated IL-6 serum levels and increased mortality after LPS-induced sepsis [>>76<<]. ADAM17—but also ADAM10—have been described to be involved in IL-6 trans-signaling by shedding IL-6 receptor (IL-6R), which in turn complexes with IL-6 and interacts with gp130-containing membrane receptors that are ubiquitously
n2:mentions
n3:16393953
Subject Item
_:vb94664184
rdf:type
n2:Context
rdf:value
been described to be involved in IL-6 trans-signaling by shedding IL-6 receptor (IL-6R), which in turn complexes with IL-6 and interacts with gp130-containing membrane receptors that are ubiquitously expressed on many cell types [>>77<<, 78].
n2:mentions
n3:21454673
Subject Item
_:vb94664185
rdf:type
n2:Context
rdf:value
been described to be involved in IL-6 trans-signaling by shedding IL-6 receptor (IL-6R), which in turn complexes with IL-6 and interacts with gp130-containing membrane receptors that are ubiquitously expressed on many cell types [77, >>78<<].
n2:mentions
n3:18490707
Subject Item
_:vb94664186
rdf:type
n2:Context
rdf:value
Most leukocytes express L-selectin on their surface, which is involved in their rolling on inflamed vascular endothelium, followed by firm adhesion and transmigration [>>79<<]. L-selectin is rapidly cleaved near the leukocyte cell surface by ADAM17 [79], during their transmigration [15].
n2:mentions
n3:15963248
Subject Item
_:vb94664187
rdf:type
n2:Context
rdf:value
L-selectin is rapidly cleaved near the leukocyte cell surface by ADAM17 [>>79<<], during their transmigration [15].
n2:mentions
n3:15963248
Subject Item
_:vb94664188
rdf:type
n2:Context
rdf:value
L-selectin is rapidly cleaved near the leukocyte cell surface by ADAM17 [79], during their transmigration [>>15<<]. ADAM17-null neutrophils show slower rolling, better adhesion and faster recruitment to site of inflammation [80] with impaired L-selectin shedding being responsible for early neutrophil recruitment [80, 81].
n2:mentions
n3:23969736
Subject Item
_:vb94664189
rdf:type
n2:Context
rdf:value
ADAM17-null neutrophils show slower rolling, better adhesion and faster recruitment to site of inflammation [>>80<<] with impaired L-selectin shedding being responsible for early neutrophil recruitment [80, 81].
n2:mentions
n3:21628404
Subject Item
_:vb94664190
rdf:type
n2:Context
rdf:value
ADAM17-null neutrophils show slower rolling, better adhesion and faster recruitment to site of inflammation [80] with impaired L-selectin shedding being responsible for early neutrophil recruitment [>>80<<, 81].
n2:mentions
n3:21628404
Subject Item
_:vb94664191
rdf:type
n2:Context
rdf:value
ADAM17-null neutrophils show slower rolling, better adhesion and faster recruitment to site of inflammation [80] with impaired L-selectin shedding being responsible for early neutrophil recruitment [80, >>81<<].
n2:mentions
n3:22623356
Subject Item
_:vb94664192
rdf:type
n2:Context
rdf:value
In mucosal barriers, ADAM17 has been shown to be important for EGFR activation, with ADAM17 or EGFR-deficient mice showing similar features [>>74<<]. Subsequently, ADAM17 was shown to be the major convertase of the EGFR ligands epiregulin, TGF-α, amphiregulin and heparin-binding EGF-like growth factors, whereas ADAM10 emerged as the major sheddase of EGF and betacellulin [82].
n2:mentions
n3:9812885
Subject Item
_:vb94664193
rdf:type
n2:Context
rdf:value
Subsequently, ADAM17 was shown to be the major convertase of the EGFR ligands epiregulin, TGF-α, amphiregulin and heparin-binding EGF-like growth factors, whereas ADAM10 emerged as the major sheddase of EGF and betacellulin [>>82<<]. In intestinal inflammation, ADAM17-dependent EGFR ligand shedding is necessary for the production of antimicrobial peptides by epithelial cells and later regeneration [15, 83]. ADAM17 has additionally been associated with shedding of
n2:mentions
n3:14993236
Subject Item
_:vb94664194
rdf:type
n2:Context
rdf:value
In intestinal inflammation, ADAM17-dependent EGFR ligand shedding is necessary for the production of antimicrobial peptides by epithelial cells and later regeneration [>>15<<, 83]. ADAM17 has additionally been associated with shedding of L-selectin from activated T cells, thereby regulating the recruitment of adaptive immune cells [74].
n2:mentions
n3:23969736
Subject Item
_:vb94664195
rdf:type
n2:Context
rdf:value
In intestinal inflammation, ADAM17-dependent EGFR ligand shedding is necessary for the production of antimicrobial peptides by epithelial cells and later regeneration [15, >>83<<]. ADAM17 has additionally been associated with shedding of L-selectin from activated T cells, thereby regulating the recruitment of adaptive immune cells [74].
n2:mentions
n3:20603312
Subject Item
_:vb94664196
rdf:type
n2:Context
rdf:value
ADAM17 has additionally been associated with shedding of L-selectin from activated T cells, thereby regulating the recruitment of adaptive immune cells [>>74<<].
n2:mentions
n3:9812885
Subject Item
_:vb94664197
rdf:type
n2:Context
rdf:value
ADAMs are also able to manipulate immune signaling via ectodomain shedding of the Notch receptor, which is required for its activation [>>84<<, 85]. Notch activation by ADAM17 was found to regulate atopic barrier function and suppress epithelial cytokine synthesis [86].
n2:mentions
n3:10882063
Subject Item
_:vb94664198
rdf:type
n2:Context
rdf:value
ADAMs are also able to manipulate immune signaling via ectodomain shedding of the Notch receptor, which is required for its activation [84, >>85<<]. Notch activation by ADAM17 was found to regulate atopic barrier function and suppress epithelial cytokine synthesis [86].
n2:mentions
n3:19726682
Subject Item
_:vb94664199
rdf:type
n2:Context
rdf:value
Notch activation by ADAM17 was found to regulate atopic barrier function and suppress epithelial cytokine synthesis [>>86<<]. In addition, ADAM17 and ADAMTS12 were shown to be involved in neutrophil apoptosis during resolution of acute inflammation [87, 88].
n2:mentions
n3:22284418
Subject Item
_:vb94664200
rdf:type
n2:Context
rdf:value
In addition, ADAM17 and ADAMTS12 were shown to be involved in neutrophil apoptosis during resolution of acute inflammation [>>87<<, 88].
n2:mentions
n3:23228566
Subject Item
_:vb94664201
rdf:type
n2:Context
rdf:value
In addition, ADAM17 and ADAMTS12 were shown to be involved in neutrophil apoptosis during resolution of acute inflammation [87, >>88<<].
n2:mentions
n3:23019333
Subject Item
_:vb94664202
rdf:type
n2:Context
rdf:value
Microglia are brain-resident immune cells that are involved in important roles of the healthy, infected and injured brain, including post-natal neurodevelopment, neural plasticity and phagocytosis [>>89<<, 90]. Upon stimulation, microglia can be polarized into different microglial subsets [91].
n2:mentions
n3:22072657
Subject Item
_:vb94664203
rdf:type
n2:Context
rdf:value
Microglia are brain-resident immune cells that are involved in important roles of the healthy, infected and injured brain, including post-natal neurodevelopment, neural plasticity and phagocytosis [89, >>90<<]. Upon stimulation, microglia can be polarized into different microglial subsets [91].
n2:mentions
n3:20012873
Subject Item
_:vb94664204
rdf:type
n2:Context
rdf:value
Upon stimulation, microglia can be polarized into different microglial subsets [>>91<<]. The polarization states can be roughly divided into classically activated (M1) microglia that adapt a pro-inflammatory phenotype by secreting TNF-α, IL-1β, IL-6 and IFNγ [92], and alternatively activated (M2) cells, which produce
n2:mentions
n3:24889886
Subject Item
_:vb94664205
rdf:type
n2:Context
rdf:value
The polarization states can be roughly divided into classically activated (M1) microglia that adapt a pro-inflammatory phenotype by secreting TNF-α, IL-1β, IL-6 and IFNγ [>>92<<], and alternatively activated (M2) cells, which produce cytokines involved in inflammation termination, restoring homeostasis and promoting tissue repair [91].
n2:mentions
n3:23252647
Subject Item
_:vb94664206
rdf:type
n2:Context
rdf:value
adapt a pro-inflammatory phenotype by secreting TNF-α, IL-1β, IL-6 and IFNγ [92], and alternatively activated (M2) cells, which produce cytokines involved in inflammation termination, restoring homeostasis and promoting tissue repair [>>91<<]. MMPs are expressed and produced by microglia at site of infection and inflammation [93, 94].
n2:mentions
n3:24889886
Subject Item
_:vb94664207
rdf:type
n2:Context
rdf:value
MMPs are expressed and produced by microglia at site of infection and inflammation [>>93<<, 94]. In macrophages, the two different subsets—M1 and M2—express different MMPs [95]. MMP-9—which depicts pro-inflammatory roles in BBB opening and cytokine activation—is secreted by M2 microglia and involved as a remodeling factor
n2:mentions
n3:12203394
Subject Item
_:vb94664208
rdf:type
n2:Context
rdf:value
MMPs are expressed and produced by microglia at site of infection and inflammation [93, >>94<<]. In macrophages, the two different subsets—M1 and M2—express different MMPs [95]. MMP-9—which depicts pro-inflammatory roles in BBB opening and cytokine activation—is secreted by M2 microglia and involved as a remodeling factor during
n2:mentions
n3:17216595
Subject Item
_:vb94664209
rdf:type
n2:Context
rdf:value
In macrophages, the two different subsets—M1 and M2—express different MMPs [>>95<<]. MMP-9—which depicts pro-inflammatory roles in BBB opening and cytokine activation—is secreted by M2 microglia and involved as a remodeling factor during repair [96, 97]. Kohkha et al. further suggest that MMPs—apart from being
n2:mentions
n3:22880008
Subject Item
_:vb94664210
rdf:type
n2:Context
rdf:value
MMP-9—which depicts pro-inflammatory roles in BBB opening and cytokine activation—is secreted by M2 microglia and involved as a remodeling factor during repair [96, >>97<<]. Kohkha et al. further suggest that MMPs—apart from being differentially expressed in M1 and M2 subsets—might also contribute to phenotype polarization by regulating cytokine and growth factor availability [15]. As microglia polarization
n2:mentions
n3:28195185
Subject Item
_:vb94664211
rdf:type
n2:Context
rdf:value
Kohkha et al. further suggest that MMPs—apart from being differentially expressed in M1 and M2 subsets—might also contribute to phenotype polarization by regulating cytokine and growth factor availability [>>15<<]. As microglia polarization towards the M2 phenotype gains interest as therapeutic strategy for different neurological disorders, understanding the critical role of metalloproteinases during this process needs further investigations.
n2:mentions
n3:23969736
Subject Item
_:vb94664212
rdf:type
n2:Context
rdf:value
neutrophil recruitment, and pro-inflammatory cytokine production—but also in inflammation termination and subsequent repair via chemokine and cytokine inactivation and involvement in angiogenesis, neurogenesis and gliosis after damage [>>98<<–101]. Therefore, inhibition of metalloproteinase during acute inflammatory processes can lead to beneficial outcomes, whereas inhibition during repair processes might be detrimental [102, 103].
n2:mentions
n3:16571756 n3:16738242 n3:16565723 n3:18621108
Subject Item
_:vb94664213
rdf:type
n2:Context
rdf:value
Therefore, inhibition of metalloproteinase during acute inflammatory processes can lead to beneficial outcomes, whereas inhibition during repair processes might be detrimental [>>102<<, 103].
n2:mentions
n3:18226583
Subject Item
_:vb94664214
rdf:type
n2:Context
rdf:value
Therefore, inhibition of metalloproteinase during acute inflammatory processes can lead to beneficial outcomes, whereas inhibition during repair processes might be detrimental [102, >>103<<].
n2:mentions
n3:17700631
Subject Item
_:vb94664215
rdf:type
n5:Section
dc:title
mmps and adams in infectious disease of the cns
n5:contains
_:vb94664344 _:vb94664345 _:vb94664346 _:vb94664347 _:vb94664348 _:vb94664349 _:vb94664350 _:vb94664336 _:vb94664337 _:vb94664338 _:vb94664339 _:vb94664340 _:vb94664341 _:vb94664342 _:vb94664343 _:vb94664328 _:vb94664329 _:vb94664330 _:vb94664331 _:vb94664332 _:vb94664333 _:vb94664334 _:vb94664335 _:vb94664320 _:vb94664321 _:vb94664322 _:vb94664323 _:vb94664324 _:vb94664325 _:vb94664326 _:vb94664327 _:vb94664248 _:vb94664249 _:vb94664250 _:vb94664251 _:vb94664252 _:vb94664253 _:vb94664254 _:vb94664255 _:vb94664240 _:vb94664241 _:vb94664242 _:vb94664243 _:vb94664244 _:vb94664245 _:vb94664246 _:vb94664247 _:vb94664232 _:vb94664233 _:vb94664234 _:vb94664235 _:vb94664236 _:vb94664237 _:vb94664238 _:vb94664239 _:vb94664224 _:vb94664225 _:vb94664226 _:vb94664227 _:vb94664228 _:vb94664229 _:vb94664230 _:vb94664231 _:vb94664216 _:vb94664217 _:vb94664218 _:vb94664219 _:vb94664220 _:vb94664221 _:vb94664222 _:vb94664223 _:vb94664312 _:vb94664313 _:vb94664314 _:vb94664315 _:vb94664316 _:vb94664317 _:vb94664318 _:vb94664319 _:vb94664304 _:vb94664305 _:vb94664306 _:vb94664307 _:vb94664308 _:vb94664309 _:vb94664310 _:vb94664311 _:vb94664296 _:vb94664297 _:vb94664298 _:vb94664299 _:vb94664300 _:vb94664301 _:vb94664302 _:vb94664303 _:vb94664288 _:vb94664289 _:vb94664290 _:vb94664291 _:vb94664292 _:vb94664293 _:vb94664294 _:vb94664295 _:vb94664280 _:vb94664281 _:vb94664282 _:vb94664283 _:vb94664284 _:vb94664285 _:vb94664286 _:vb94664287 _:vb94664272 _:vb94664273 _:vb94664274 _:vb94664275 _:vb94664276 _:vb94664277 _:vb94664278 _:vb94664279 _:vb94664264 _:vb94664265 _:vb94664266 _:vb94664267 _:vb94664268 _:vb94664269 _:vb94664270 _:vb94664271 _:vb94664256 _:vb94664257 _:vb94664258 _:vb94664259 _:vb94664260 _:vb94664261 _:vb94664262 _:vb94664263
Subject Item
_:vb94664216
rdf:type
n2:Context
rdf:value
[>>128<<
n2:mentions
n3:10639424
Subject Item
_:vb94664217
rdf:type
n2:Context
rdf:value
[>>177<<
n2:mentions
n3:25576979
Subject Item
_:vb94664218
rdf:type
n2:Context
rdf:value
[>>172<<
n2:mentions
n3:9778257
Subject Item
_:vb94664219
rdf:type
n2:Context
rdf:value
[>>169<<
n2:mentions
n3:25551808
Subject Item
_:vb94664220
rdf:type
n2:Context
rdf:value
The most common causative agents of bacterial meningitis—Streptococcus pneumoniae, Neisseria meningitidis and Haemophilus influenzae type b [>>106<<]—colonize the human nasopharynx and are transmitted via the respiratory route [105].
n2:mentions
n3:27062097
Subject Item
_:vb94664221
rdf:type
n2:Context
rdf:value
Among bacterial meningitis, pneumococcal meningitis (PM) is especially detrimental as it causes high mortality and leads to long-lasting neurofunctional deficits [>>107<<, 108]. Neurofunctional sequelae after PM include hearing loss, epilepsy, cerebral palsy, as well as behavioral and cognitive deficits [107–109].
n2:mentions
n3:12467688
Subject Item
_:vb94664222
rdf:type
n2:Context
rdf:value
Among bacterial meningitis, pneumococcal meningitis (PM) is especially detrimental as it causes high mortality and leads to long-lasting neurofunctional deficits [107, >>108<<]. Neurofunctional sequelae after PM include hearing loss, epilepsy, cerebral palsy, as well as behavioral and cognitive deficits [107–109].
n2:mentions
n3:20417414
Subject Item
_:vb94664223
rdf:type
n2:Context
rdf:value
Neurofunctional sequelae after PM include hearing loss, epilepsy, cerebral palsy, as well as behavioral and cognitive deficits [>>107<<–109]. Brain damage during PM is characterized by cortical necrosis and apoptosis of dentate gyrus granular cell progenitors in the hippocampus, being in part responsible for behavioral and cognitive deficits [110–114]. In experimental
n2:mentions
n3:20417414 n3:12467688 n3:20610819
Subject Item
_:vb94664224
rdf:type
n2:Context
rdf:value
Brain damage during PM is characterized by cortical necrosis and apoptosis of dentate gyrus granular cell progenitors in the hippocampus, being in part responsible for behavioral and cognitive deficits [>>110<<–114]. In experimental models, cortical necrosis is found as early as 18 h after infection and might arise as a consequence of focal and global ischemia [107, 115]. Neural cell death is caused by multiple factors including bacterial toxins
n2:mentions
n3:11110643 n3:11801337 n3:12788989 n3:11109000 n3:10197818
Subject Item
_:vb94664225
rdf:type
n2:Context
rdf:value
In experimental models, cortical necrosis is found as early as 18 h after infection and might arise as a consequence of focal and global ischemia [>>107<<, 115]. Neural cell death is caused by multiple factors including bacterial toxins and an excessive inflammatory reaction from the host [105, 116–118]. Inflammatory mediators (cytokines, chemokines, reactive oxygen and nitrogen species,
n2:mentions
n3:12467688
Subject Item
_:vb94664226
rdf:type
n2:Context
rdf:value
In experimental models, cortical necrosis is found as early as 18 h after infection and might arise as a consequence of focal and global ischemia [107, >>115<<]. Neural cell death is caused by multiple factors including bacterial toxins and an excessive inflammatory reaction from the host [105, 116–118]. Inflammatory mediators (cytokines, chemokines, reactive oxygen and nitrogen species, MMPs)
n2:mentions
n3:20442574
Subject Item
_:vb94664227
rdf:type
n2:Context
rdf:value
Neural cell death is caused by multiple factors including bacterial toxins and an excessive inflammatory reaction from the host [105, >>116<<–118]. Inflammatory mediators (cytokines, chemokines, reactive oxygen and nitrogen species, MMPs) released from recruited neutrophils, endothelial cells, leptomeningeal macrophages and brain-resident microglia and astrocytes contribute to
n2:mentions
n3:12677451 n3:21734248 n3:15529270
Subject Item
_:vb94664228
rdf:type
n2:Context
rdf:value
species, MMPs) released from recruited neutrophils, endothelial cells, leptomeningeal macrophages and brain-resident microglia and astrocytes contribute to pathogen eradication but also act as neurotoxins and induce neuronal damage [>>107<<, 116, 119, 120]. Moreover, PM induces damage to hair cells and spiral ganglion neurons in the inner ear [121–123] provoking sensorineural hearing impairments in up to 30% of survivors [108, 124, 125].
n2:mentions
n3:12467688
Subject Item
_:vb94664229
rdf:type
n2:Context
rdf:value
MMPs) released from recruited neutrophils, endothelial cells, leptomeningeal macrophages and brain-resident microglia and astrocytes contribute to pathogen eradication but also act as neurotoxins and induce neuronal damage [107, >>116<<, 119, 120]. Moreover, PM induces damage to hair cells and spiral ganglion neurons in the inner ear [121–123] provoking sensorineural hearing impairments in up to 30% of survivors [108, 124, 125].
n2:mentions
n3:21734248
Subject Item
_:vb94664230
rdf:type
n2:Context
rdf:value
MMPs) released from recruited neutrophils, endothelial cells, leptomeningeal macrophages and brain-resident microglia and astrocytes contribute to pathogen eradication but also act as neurotoxins and induce neuronal damage [107, 116, >>119<<, 120]. Moreover, PM induces damage to hair cells and spiral ganglion neurons in the inner ear [121–123] provoking sensorineural hearing impairments in up to 30% of survivors [108, 124, 125].
n2:mentions
n3:14688201
Subject Item
_:vb94664231
rdf:type
n2:Context
rdf:value
released from recruited neutrophils, endothelial cells, leptomeningeal macrophages and brain-resident microglia and astrocytes contribute to pathogen eradication but also act as neurotoxins and induce neuronal damage [107, 116, 119, >>120<<]. Moreover, PM induces damage to hair cells and spiral ganglion neurons in the inner ear [121–123] provoking sensorineural hearing impairments in up to 30% of survivors [108, 124, 125].
n2:mentions
n3:18569457
Subject Item
_:vb94664232
rdf:type
n2:Context
rdf:value
Moreover, PM induces damage to hair cells and spiral ganglion neurons in the inner ear [>>121<<–123] provoking sensorineural hearing impairments in up to 30% of survivors [108, 124, 125].
n2:mentions
n3:28460251 n3:27445150 n3:12744466
Subject Item
_:vb94664233
rdf:type
n2:Context
rdf:value
Moreover, PM induces damage to hair cells and spiral ganglion neurons in the inner ear [121–123] provoking sensorineural hearing impairments in up to 30% of survivors [>>108<<, 124, 125].
n2:mentions
n3:20417414
Subject Item
_:vb94664234
rdf:type
n2:Context
rdf:value
Moreover, PM induces damage to hair cells and spiral ganglion neurons in the inner ear [121–123] provoking sensorineural hearing impairments in up to 30% of survivors [108, >>124<<, 125]. In an infant rat PM model, increased CSF levels of TNF-α during acute infection were positively correlated with increased hearing loss in surviving animals [122].
n2:mentions
n3:15509818
Subject Item
_:vb94664235
rdf:type
n2:Context
rdf:value
Moreover, PM induces damage to hair cells and spiral ganglion neurons in the inner ear [121–123] provoking sensorineural hearing impairments in up to 30% of survivors [108, 124, >>125<<]. In an infant rat PM model, increased CSF levels of TNF-α during acute infection were positively correlated with increased hearing loss in surviving animals [122].
n2:mentions
n3:20683377
Subject Item
_:vb94664236
rdf:type
n2:Context
rdf:value
In an infant rat PM model, increased CSF levels of TNF-α during acute infection were positively correlated with increased hearing loss in surviving animals [>>122<<].
n2:mentions
n3:27445150
Subject Item
_:vb94664237
rdf:type
n2:Context
rdf:value
Upon bacterial invasion into the CNS, a wide range of cytokine is produced and secreted into the CSF [>>126<<]. In experimental pneumococcal meningitis, increased CSF levels of TNF-α and MMP-9 are already detected at 4 h after infection and peaked at 12 h after infection [127]. Since levels of TNF-α, IL-1β, IL-6 and IL-8 in the CSF increase
n2:mentions
n3:8945522
Subject Item
_:vb94664238
rdf:type
n2:Context
rdf:value
In experimental pneumococcal meningitis, increased CSF levels of TNF-α and MMP-9 are already detected at 4 h after infection and peaked at 12 h after infection [>>127<<]. Since levels of TNF-α, IL-1β, IL-6 and IL-8 in the CSF increase before evidence of neutrophil recruitment, brain-resident cells are considered to contribute significantly to cytokine production [126]. As a result of bacterial
n2:mentions
n3:11522576
Subject Item
_:vb94664239
rdf:type
n2:Context
rdf:value
Since levels of TNF-α, IL-1β, IL-6 and IL-8 in the CSF increase before evidence of neutrophil recruitment, brain-resident cells are considered to contribute significantly to cytokine production [>>126<<]. As a result of bacterial proliferation, an excessive inflammatory reaction takes place in the CSF with BBB breakdown causing brain edema via leakage of plasma into the CNS, increased intracranial pressure, hydrocephalus and cerebral
n2:mentions
n3:8945522
Subject Item
_:vb94664240
rdf:type
n2:Context
rdf:value
of bacterial proliferation, an excessive inflammatory reaction takes place in the CSF with BBB breakdown causing brain edema via leakage of plasma into the CNS, increased intracranial pressure, hydrocephalus and cerebral ischemia [>>116<<]. In patients with bacterial meningitis, cerebrovascular complications are frequently observed [124] with vasculitis being the cause for cerebral infarction, hemorrhages and subsequent cortical damage during meningitis [18, 116, 124].
n2:mentions
n3:21734248
Subject Item
_:vb94664241
rdf:type
n2:Context
rdf:value
In patients with bacterial meningitis, cerebrovascular complications are frequently observed [>>124<<] with vasculitis being the cause for cerebral infarction, hemorrhages and subsequent cortical damage during meningitis [18, 116, 124].
n2:mentions
n3:15509818
Subject Item
_:vb94664242
rdf:type
n2:Context
rdf:value
In patients with bacterial meningitis, cerebrovascular complications are frequently observed [124] with vasculitis being the cause for cerebral infarction, hemorrhages and subsequent cortical damage during meningitis [>>18<<, 116, 124].
n2:mentions
n3:25410364
Subject Item
_:vb94664243
rdf:type
n2:Context
rdf:value
In patients with bacterial meningitis, cerebrovascular complications are frequently observed [124] with vasculitis being the cause for cerebral infarction, hemorrhages and subsequent cortical damage during meningitis [18, >>116<<, 124].
n2:mentions
n3:21734248
Subject Item
_:vb94664244
rdf:type
n2:Context
rdf:value
In patients with bacterial meningitis, cerebrovascular complications are frequently observed [124] with vasculitis being the cause for cerebral infarction, hemorrhages and subsequent cortical damage during meningitis [18, 116, >>124<<].
n2:mentions
n3:15509818
Subject Item
_:vb94664245
rdf:type
n2:Context
rdf:value
in response to the invading pathogen—contribute to acute neuroinflammatory reaction and damage upon bacterial invasion but might also be involved later during the disease in the resolution of inflammation and repair mechanisms [>>41<<, 127–129]. During bacterial meningitis, the expression and activation of metalloproteinases and their inhibitors are altered compared to physiologic conditions.
n2:mentions
n3:10430840
Subject Item
_:vb94664246
rdf:type
n2:Context
rdf:value
in response to the invading pathogen—contribute to acute neuroinflammatory reaction and damage upon bacterial invasion but might also be involved later during the disease in the resolution of inflammation and repair mechanisms [41, >>127<<–129]. During bacterial meningitis, the expression and activation of metalloproteinases and their inhibitors are altered compared to physiologic conditions.
n2:mentions
n3:10639424 n3:11522576 n3:19161911
Subject Item
_:vb94664247
rdf:type
n2:Context
rdf:value
In brain tissue, expression of MMP-3, -8, -9, -12, -13 and -14 was significantly upregulated (100- to 1000-fold), while expression levels of MMP-2 and MMP-7 remained unchanged [>>127<<]. The upregulation of MMP-8 (mostly released from infiltrating neutrophils) is a specific hallmark of bacterial meningitis, which is not found in other neuroinflammatory disease [130]. MMP-8 induces increased barrier permeability via
n2:mentions
n3:11522576
Subject Item
_:vb94664248
rdf:type
n2:Context
rdf:value
The upregulation of MMP-8 (mostly released from infiltrating neutrophils) is a specific hallmark of bacterial meningitis, which is not found in other neuroinflammatory disease [>>130<<]. MMP-8 induces increased barrier permeability via proteolytic cleavage of the tight junction protein occludin in meningococcal neuroinfection [131]. Other experimental data of meningitis caused by heat-inactivated N. meningitidis showed
n2:mentions
n3:11690622
Subject Item
_:vb94664249
rdf:type
n2:Context
rdf:value
MMP-8 induces increased barrier permeability via proteolytic cleavage of the tight junction protein occludin in meningococcal neuroinfection [>>131<<]. Other experimental data of meningitis caused by heat-inactivated N. meningitidis showed a significant upregulation of MMP-9 mRNA expression with stable MMP-2 and MMP-7 expression [41]. On the protein level, MMP-9 in the CSF correlated
n2:mentions
n3:20442866
Subject Item
_:vb94664250
rdf:type
n2:Context
rdf:value
Other experimental data of meningitis caused by heat-inactivated N. meningitidis showed a significant upregulation of MMP-9 mRNA expression with stable MMP-2 and MMP-7 expression [>>41<<]. On the protein level, MMP-9 in the CSF correlated with TNF-α levels, with a concentration peak for both at 12 h after intracisternal infection with S. pneumoniae [127]. MMP-9 in the CSF was detected as early as 15 min after
n2:mentions
n3:10430840
Subject Item
_:vb94664251
rdf:type
n2:Context
rdf:value
On the protein level, MMP-9 in the CSF correlated with TNF-α levels, with a concentration peak for both at 12 h after intracisternal infection with S. pneumoniae [>>127<<]. MMP-9 in the CSF was detected as early as 15 min after intracisternal infection, indicating its early release from brain-resident cells in this experimental model. Further recruitment and infiltration of neutrophils contribute to the
n2:mentions
n3:11522576
Subject Item
_:vb94664252
rdf:type
n2:Context
rdf:value
Further recruitment and infiltration of neutrophils contribute to the peak MMP-9 levels at 12 h after infection [>>127<<]. Gelatinase activity (MMP-2 and/or MMP-9) has been associated with the occurrence of cortical necrotic lesions in experimental PM [23, 132]. During the initiation of neuroinflammation, ADAM17 plays a crucial role in releasing TNF-α,
n2:mentions
n3:11522576
Subject Item
_:vb94664253
rdf:type
n2:Context
rdf:value
Gelatinase activity (MMP-2 and/or MMP-9) has been associated with the occurrence of cortical necrotic lesions in experimental PM [>>23<<, 132]. During the initiation of neuroinflammation, ADAM17 plays a crucial role in releasing TNF-α, which in turn acts as a stimulus to induce MMP upregulation via a positive feedback loop [127, 133]. The fact that MMP-7—being the second
n2:mentions
n3:16257222
Subject Item
_:vb94664254
rdf:type
n2:Context
rdf:value
Gelatinase activity (MMP-2 and/or MMP-9) has been associated with the occurrence of cortical necrotic lesions in experimental PM [23, >>132<<]. During the initiation of neuroinflammation, ADAM17 plays a crucial role in releasing TNF-α, which in turn acts as a stimulus to induce MMP upregulation via a positive feedback loop [127, 133]. The fact that MMP-7—being the second most
n2:mentions
n3:15145598
Subject Item
_:vb94664255
rdf:type
n2:Context
rdf:value
During the initiation of neuroinflammation, ADAM17 plays a crucial role in releasing TNF-α, which in turn acts as a stimulus to induce MMP upregulation via a positive feedback loop [>>127<<, 133]. The fact that MMP-7—being the second most potent TNF-α activator apart from ADAM17 [65]—remains unchanged in bacterial meningitis [127] emphasizes the importance of ADAM17 during this early neuroinflammatory process. In addition to
n2:mentions
n3:11522576
Subject Item
_:vb94664256
rdf:type
n2:Context
rdf:value
During the initiation of neuroinflammation, ADAM17 plays a crucial role in releasing TNF-α, which in turn acts as a stimulus to induce MMP upregulation via a positive feedback loop [127, >>133<<]. The fact that MMP-7—being the second most potent TNF-α activator apart from ADAM17 [65]—remains unchanged in bacterial meningitis [127] emphasizes the importance of ADAM17 during this early neuroinflammatory process. In addition to
n2:mentions
n3:9042108
Subject Item
_:vb94664257
rdf:type
n2:Context
rdf:value
The fact that MMP-7—being the second most potent TNF-α activator apart from ADAM17 [>>65<<]—remains unchanged in bacterial meningitis [127] emphasizes the importance of ADAM17 during this early neuroinflammatory process.
n2:mentions
n3:12135369
Subject Item
_:vb94664258
rdf:type
n2:Context
rdf:value
The fact that MMP-7—being the second most potent TNF-α activator apart from ADAM17 [65]—remains unchanged in bacterial meningitis [>>127<<] emphasizes the importance of ADAM17 during this early neuroinflammatory process.
n2:mentions
n3:11522576
Subject Item
_:vb94664259
rdf:type
n2:Context
rdf:value
In addition to increased TNF-α and MMP-9 levels, TIMP-1 expression is also increased in the CSF of infant rats with PM, however, with a short delay [>>23<<]. TIMPs are suggested to regulate protein degradation and cytokine shedding during PM, thereby controlling metalloproteinase-induced neuroinflammation. In experimental PM, the upregulation of MMP-9, however, exceeds the compensatory
n2:mentions
n3:16257222
Subject Item
_:vb94664260
rdf:type
n2:Context
rdf:value
This imbalance between MMPs and TIMPs during bacterial meningitis has, therefore, been implicated as a key event during pathophysiology of the disease [>>23<<]. In an experimental model of cerebral ischemia, MMP-9-deficient mice showed BBB preservation and reduced levels of tight junction protein degradation with subsequent better outcome [134]. MMP-9 deficiency during experimental PM, however,
n2:mentions
n3:16257222
Subject Item
_:vb94664261
rdf:type
n2:Context
rdf:value
In an experimental model of cerebral ischemia, MMP-9-deficient mice showed BBB preservation and reduced levels of tight junction protein degradation with subsequent better outcome [>>134<<]. MMP-9 deficiency during experimental PM, however, was shown to be associated with impaired bacterial clearance from blood and spleen, without showing an impact on clinical course of the disease, leukocyte infiltration of the
n2:mentions
n3:11567062
Subject Item
_:vb94664262
rdf:type
n2:Context
rdf:value
was shown to be associated with impaired bacterial clearance from blood and spleen, without showing an impact on clinical course of the disease, leukocyte infiltration of the subarachnoid space or bacterial titers in the brain [>>135<<]. Non-infectious experimental models of brain damage have shown a direct effect of MMP-9 on laminin degradation and associated hippocampal apoptosis [136, 137].
n2:mentions
n3:12581831
Subject Item
_:vb94664263
rdf:type
n2:Context
rdf:value
Non-infectious experimental models of brain damage have shown a direct effect of MMP-9 on laminin degradation and associated hippocampal apoptosis [>>136<<, 137].
n2:mentions
n3:16000631
Subject Item
_:vb94664264
rdf:type
n2:Context
rdf:value
Non-infectious experimental models of brain damage have shown a direct effect of MMP-9 on laminin degradation and associated hippocampal apoptosis [136, >>137<<].
n2:mentions
n3:20033829
Subject Item
_:vb94664265
rdf:type
n2:Context
rdf:value
In patients with bacterial meningitis, CSF levels of MMP-1, -3, -7, -8, -9 and -10 have been found to be elevated, whereas CSF levels of MMP-2 remain unaffected [>>35<<, 138–143].
n2:mentions
n3:10913401
Subject Item
_:vb94664266
rdf:type
n2:Context
rdf:value
In patients with bacterial meningitis, CSF levels of MMP-1, -3, -7, -8, -9 and -10 have been found to be elevated, whereas CSF levels of MMP-2 remain unaffected [35, >>138<<–143]. Similar to animal models, TIMP-1 levels have also been found to be upregulated, whereas TIMP-4 was significantly downregulated compared to control patients [142]. One week after infection, TIMP-1 continues to be highly expressed,
n2:mentions
n3:11024556 n3:12480084 n3:25960946 n3:21521415 n3:16640649 n3:21300974
Subject Item
_:vb94664267
rdf:type
n2:Context
rdf:value
Similar to animal models, TIMP-1 levels have also been found to be upregulated, whereas TIMP-4 was significantly downregulated compared to control patients [>>142<<]. One week after infection, TIMP-1 continues to be highly expressed, whereas MMP-9 is reduced compared to the acute phase of infection [144]. In pediatric PM, MMP-9 levels were found to correlate with CSF cell counts, with high CSF MMP-9
n2:mentions
n3:21521415
Subject Item
_:vb94664268
rdf:type
n2:Context
rdf:value
One week after infection, TIMP-1 continues to be highly expressed, whereas MMP-9 is reduced compared to the acute phase of infection [>>144<<]. In pediatric PM, MMP-9 levels were found to correlate with CSF cell counts, with high CSF MMP-9 levels being a risk factor for fatal outcome or development of neurologic sequelae [35, 141, 144]. The causative pathogen determines the
n2:mentions
n3:25903567
Subject Item
_:vb94664269
rdf:type
n2:Context
rdf:value
In pediatric PM, MMP-9 levels were found to correlate with CSF cell counts, with high CSF MMP-9 levels being a risk factor for fatal outcome or development of neurologic sequelae [>>35<<, 141, 144].
n2:mentions
n3:10913401
Subject Item
_:vb94664270
rdf:type
n2:Context
rdf:value
In pediatric PM, MMP-9 levels were found to correlate with CSF cell counts, with high CSF MMP-9 levels being a risk factor for fatal outcome or development of neurologic sequelae [35, >>141<<, 144]. The causative pathogen determines the inflammatory response in patients with bacterial meningitis. Pneumococcal meningitis is associated with significantly increased mortality and elevated levels of IFN-γ, MCP-1 and MMP-9 compared
n2:mentions
n3:21300974
Subject Item
_:vb94664271
rdf:type
n2:Context
rdf:value
In pediatric PM, MMP-9 levels were found to correlate with CSF cell counts, with high CSF MMP-9 levels being a risk factor for fatal outcome or development of neurologic sequelae [35, 141, >>144<<]. The causative pathogen determines the inflammatory response in patients with bacterial meningitis. Pneumococcal meningitis is associated with significantly increased mortality and elevated levels of IFN-γ, MCP-1 and MMP-9 compared to
n2:mentions
n3:25903567
Subject Item
_:vb94664272
rdf:type
n2:Context
rdf:value
Tuberculous meningitis (TBM), which arises rarely as an extrapulmonary form of tuberculosis, is associated with neurofunctional complications [>>146<<]. In patients with TBM, levels of MMP-2 and MMP-9 were found to be elevated, and high levels of MMP-9 were associated with late neurofunctional deficits [147, 148].
n2:mentions
n3:27385155
Subject Item
_:vb94664273
rdf:type
n2:Context
rdf:value
In patients with TBM, levels of MMP-2 and MMP-9 were found to be elevated, and high levels of MMP-9 were associated with late neurofunctional deficits [>>147<<, 148]. Adjuvant dexamethasone during TBM was shown to reduce MMP-9 levels early in treatment and might represent one way by which dexamethasone reduces mortality in TBM [149, 150]. Despite the beneficial effect of dexamethasone in terms
n2:mentions
n3:15140609
Subject Item
_:vb94664274
rdf:type
n2:Context
rdf:value
In patients with TBM, levels of MMP-2 and MMP-9 were found to be elevated, and high levels of MMP-9 were associated with late neurofunctional deficits [147, >>148<<]. Adjuvant dexamethasone during TBM was shown to reduce MMP-9 levels early in treatment and might represent one way by which dexamethasone reduces mortality in TBM [149, 150]. Despite the beneficial effect of dexamethasone in terms of
n2:mentions
n3:27899068
Subject Item
_:vb94664275
rdf:type
n2:Context
rdf:value
Adjuvant dexamethasone during TBM was shown to reduce MMP-9 levels early in treatment and might represent one way by which dexamethasone reduces mortality in TBM [>>149<<, 150]. Despite the beneficial effect of dexamethasone in terms of mortality, it could not successfully prevent severe disabilities [150].
n2:mentions
n3:19789647
Subject Item
_:vb94664276
rdf:type
n2:Context
rdf:value
Adjuvant dexamethasone during TBM was shown to reduce MMP-9 levels early in treatment and might represent one way by which dexamethasone reduces mortality in TBM [149, >>150<<]. Despite the beneficial effect of dexamethasone in terms of mortality, it could not successfully prevent severe disabilities [150].
n2:mentions
n3:15496623
Subject Item
_:vb94664277
rdf:type
n2:Context
rdf:value
Despite the beneficial effect of dexamethasone in terms of mortality, it could not successfully prevent severe disabilities [>>150<<].
n2:mentions
n3:15496623
Subject Item
_:vb94664278
rdf:type
n2:Context
rdf:value
The involvement of metalloproteinase in BBB integrity during viral neuroinfections has been intensively reviewed elsewhere [>>151<<]. Clinical data from patients with viral meningitis report elevated CSF levels of MMP-9 and TIMP-1 compared to control patients, with MMP-9 levels correlating to neutrophil cell number in CSF [152].
n2:mentions
n3:22564250
Subject Item
_:vb94664279
rdf:type
n2:Context
rdf:value
Clinical data from patients with viral meningitis report elevated CSF levels of MMP-9 and TIMP-1 compared to control patients, with MMP-9 levels correlating to neutrophil cell number in CSF [>>152<<]. Involvement of metalloproteinases during viral neuroinfection has mostly been analyzed in experimental studies, though.
n2:mentions
n3:9628456
Subject Item
_:vb94664280
rdf:type
n2:Context
rdf:value
Japanese encephalitis virus (JEV) is an arthropod-borne virus and a major cause of acute encephalopathy in children [>>153<<]. In vitro, MMP-9 expression after JEV infection is mediated via NF-κB activation and the generation of ROS [153].
n2:mentions
n3:20698853
Subject Item
_:vb94664281
rdf:type
n2:Context
rdf:value
In vitro, MMP-9 expression after JEV infection is mediated via NF-κB activation and the generation of ROS [>>153<<]. The expression of MMP-2, -7 and -9, as well as TIMP-1 and -3 is upregulated in mice infected with JEV and their overexpression is associated with disease severity [154].
n2:mentions
n3:20698853
Subject Item
_:vb94664282
rdf:type
n2:Context
rdf:value
The expression of MMP-2, -7 and -9, as well as TIMP-1 and -3 is upregulated in mice infected with JEV and their overexpression is associated with disease severity [>>154<<].
n2:mentions
n3:22441541
Subject Item
_:vb94664283
rdf:type
n2:Context
rdf:value
In experimental herpes-simplex virus encephalitis (HSE), MMP-9 is upregulated and insufficiently counterbalanced by TIMP-1 resulting in a loss of collagen type IV, indicating MMP-9’s role during the pathogenesis of HSE [>>155<<].
n2:mentions
n3:17109833
Subject Item
_:vb94664284
rdf:type
n2:Context
rdf:value
In vitro, West Nile virus (WNV)-infected human endothelial cells show significant upregulation of multiple MMPs with subsequent loss of tight junction proteins, an effect successfully prevented by the MMP inhibitor GM6001 [>>156<<]. MMP-9 levels are also found to be elevated in WNV-infected mice as well as in patients, suggesting that MMP-9 plays a role in mediating WNV entry into the CNS [157].
n2:mentions
n3:19922973
Subject Item
_:vb94664285
rdf:type
n2:Context
rdf:value
MMP-9 levels are also found to be elevated in WNV-infected mice as well as in patients, suggesting that MMP-9 plays a role in mediating WNV entry into the CNS [>>157<<].
n2:mentions
n3:18632868
Subject Item
_:vb94664286
rdf:type
n2:Context
rdf:value
In vitro, this mechanism seems to rely on MMP-2 and -9 upregulation with an associated reduction of tight junction proteins [>>158<<]. In experimental HIV infection, the envelope protein gp120 increased MMP-2 and -9 expression with subsequent laminin and claudin-5 reduction and causing increased BBB permeability [159]. In patients with HIV-associated dementia, CSF
n2:mentions
n3:16436595
Subject Item
_:vb94664287
rdf:type
n2:Context
rdf:value
In experimental HIV infection, the envelope protein gp120 increased MMP-2 and -9 expression with subsequent laminin and claudin-5 reduction and causing increased BBB permeability [>>159<<]. In patients with HIV-associated dementia, CSF levels of MMP-2, -7 and 9 are increased and might reflect a link to symptomatic neurological disease [160, 161]. Increased MMP activity with its detrimental effects on BBB integrity might
n2:mentions
n3:20613638
Subject Item
_:vb94664288
rdf:type
n2:Context
rdf:value
In patients with HIV-associated dementia, CSF levels of MMP-2, -7 and 9 are increased and might reflect a link to symptomatic neurological disease [>>160<<, 161]. Increased MMP activity with its detrimental effects on BBB integrity might contribute to transendothelial migration of HIV-infected cells into the CNS and development of HIV-associated neurologic damage [161].
n2:mentions
n3:10482270
Subject Item
_:vb94664289
rdf:type
n2:Context
rdf:value
In patients with HIV-associated dementia, CSF levels of MMP-2, -7 and 9 are increased and might reflect a link to symptomatic neurological disease [160, >>161<<]. Increased MMP activity with its detrimental effects on BBB integrity might contribute to transendothelial migration of HIV-infected cells into the CNS and development of HIV-associated neurologic damage [161].
n2:mentions
n3:10822329
Subject Item
_:vb94664290
rdf:type
n2:Context
rdf:value
Increased MMP activity with its detrimental effects on BBB integrity might contribute to transendothelial migration of HIV-infected cells into the CNS and development of HIV-associated neurologic damage [>>161<<].
n2:mentions
n3:10822329
Subject Item
_:vb94664291
rdf:type
n2:Context
rdf:value
Mouse adenovirus type-1 (MAV-1) infection increases levels of MMP-2 and -9 in brains [>>162<<]. Additional ex vivo data revealed that MMP-2 and -9 are produced by astrocytes and microglia in response to mouse encephalitic adenovirus-1, which might contribute to BBB disruption and encephalitis [163].
n2:mentions
n3:27303733
Subject Item
_:vb94664292
rdf:type
n2:Context
rdf:value
Additional ex vivo data revealed that MMP-2 and -9 are produced by astrocytes and microglia in response to mouse encephalitic adenovirus-1, which might contribute to BBB disruption and encephalitis [>>163<<]. MAV-1 may also induce BBB breakdown by reducing surface expression of TJ proteins occludin and claudin-5 [164]. Murine coronavirus-induced viral encephalitis induces expression of MMP-3 and -12 plus TIMP-1, with MMP-3 expression
n2:mentions
n3:28053109
Subject Item
_:vb94664293
rdf:type
n2:Context
rdf:value
MAV-1 may also induce BBB breakdown by reducing surface expression of TJ proteins occludin and claudin-5 [>>164<<]. Murine coronavirus-induced viral encephalitis induces expression of MMP-3 and -12 plus TIMP-1, with MMP-3 expression exclusively localized in astrocytes, whereas TIMP-1 originates from infiltrating cells [165]. Increased MMP and TIMP
n2:mentions
n3:19570856
Subject Item
_:vb94664294
rdf:type
n2:Context
rdf:value
Murine coronavirus-induced viral encephalitis induces expression of MMP-3 and -12 plus TIMP-1, with MMP-3 expression exclusively localized in astrocytes, whereas TIMP-1 originates from infiltrating cells [>>165<<]. Increased MMP and TIMP levels are also associated with increased viral replication during neurotropic mouse hepatitis infection [166].
n2:mentions
n3:15795262
Subject Item
_:vb94664295
rdf:type
n2:Context
rdf:value
Increased MMP and TIMP levels are also associated with increased viral replication during neurotropic mouse hepatitis infection [>>166<<].
n2:mentions
n3:12097550
Subject Item
_:vb94664296
rdf:type
n2:Context
rdf:value
apoptosis ↓, learning/memory ↑[>>127<<]TNF484 (pretreatment)Broad spectrum plus ADAM17Rat-PMCortical necrosis ↓, seizures ↓, TNF-α ↓, collagen deg.
n2:mentions
n3:11522576
Subject Item
_:vb94664297
rdf:type
n2:Context
rdf:value
↓Mortality ↑ for high dose[>>132<<]Ro 32-7315 (3 hpi)ADAM17 > broad spectrumRat-PMCortical necrosis ↓, hippo.
n2:mentions
n3:15145598
Subject Item
_:vb94664298
rdf:type
n2:Context
rdf:value
↓Mortality ↑ for high dose[132]Ro 32-7315 (3 hpi)ADAM17 > broad spectrumRat-PMCortical necrosis ↓, hippo. apoptosis ↓, weight loss ↓, TNF-α ↓, IL-6 ↓Mortality ↑Yes[>>167<<
n2:mentions
n3:24491581
Subject Item
_:vb94664299
rdf:type
n2:Context
rdf:value
gelatinaseRat-PMCortical necrosis ↓, hippo. apoptosis ↓, mortality ↓, TNF-α ↓, IL-1β ↓, collagen deg. ↓Yes[>>167<<]RS-130830 (3 hpi)MMP-2, -3, -8, -9, -12, -13 and -14Rat-PMCortical necrosis ↓, IL-1β ↓, IL-10 ↓, weight loss ↓, CSF WBCs ↓Yes[168]Doxycycline (symptom onset)Broad spectrum plus ADAM17Rat-PMCortical necrosis ↓, mortality ↓, TNF-α ↓, BBB
n2:mentions
n3:24491581
Subject Item
_:vb94664300
rdf:type
n2:Context
rdf:value
and -14Rat-PMCortical necrosis ↓, IL-1β ↓, IL-10 ↓, weight loss ↓, CSF WBCs ↓Yes[168]Doxycycline (symptom onset)Broad spectrum plus ADAM17Rat-PMCortical necrosis ↓, mortality ↓, TNF-α ↓, BBB breakdown ↓, SGN loss ↓, hearing loss ↓Yes[>>173<<]Trocade™ + Daptomycin (symptom onset)Colagenase, part. gelatinase, bacteriolysis inhibitionRat-PMCortical necrosis ↓, hippo.
n2:mentions
n3:16790761
Subject Item
_:vb94664301
rdf:type
n2:Context
rdf:value
apoptosis ↓, clinical status ↑, TNF-α ↓, IL-6 ↓, IL-1β ↓, IL-10 ↓, learning and memory ↑, hearing loss ↓, bacillary clearance ↑Yes[174]SB-3CTGelatinasesMouse-TBMMMP-9 ↓, bacillary clearance ↑[>>146<<
n2:mentions
n3:27385155
Subject Item
_:vb94664302
rdf:type
n2:Context
rdf:value
Matrix metalloproteinases and ADAMs function as ECM degrading enzymes and sheddases, thereby controlling BBB breakdown and production of inflammatory cytokines [>>15<<]. In experimental bacterial meningitis, MMP and ADAM inhibitors significantly reduce CSF levels of MMPs and pro-inflammatory cytokines (TNF-α, IL-6, IL-1β, IL-10) [128, 132, 167–169].
n2:mentions
n3:23969736
Subject Item
_:vb94664303
rdf:type
n2:Context
rdf:value
In experimental bacterial meningitis, MMP and ADAM inhibitors significantly reduce CSF levels of MMPs and pro-inflammatory cytokines (TNF-α, IL-6, IL-1β, IL-10) [>>128<<, 132, 167–169].
n2:mentions
n3:10639424
Subject Item
_:vb94664304
rdf:type
n2:Context
rdf:value
In experimental bacterial meningitis, MMP and ADAM inhibitors significantly reduce CSF levels of MMPs and pro-inflammatory cytokines (TNF-α, IL-6, IL-1β, IL-10) [128, >>132<<, 167–169].
n2:mentions
n3:15145598
Subject Item
_:vb94664305
rdf:type
n2:Context
rdf:value
In experimental bacterial meningitis, MMP and ADAM inhibitors significantly reduce CSF levels of MMPs and pro-inflammatory cytokines (TNF-α, IL-6, IL-1β, IL-10) [128, 132, >>167<<–169]. Notably, CSF levels of TNF-α are also significantly reduced by MMP inhibitors (MMPIs) without specificity for ADAM17 (i.e., Trocade) [167], indicating that MMPIs are able to indirectly reduce pro-inflammatory cytokine production
n2:mentions
n3:24491581 n3:25551808
Subject Item
_:vb94664306
rdf:type
n2:Context
rdf:value
Notably, CSF levels of TNF-α are also significantly reduced by MMP inhibitors (MMPIs) without specificity for ADAM17 (i.e., Trocade) [>>167<<], indicating that MMPIs are able to indirectly reduce pro-inflammatory cytokine production apart from direct ADAM17 inhibition.
n2:mentions
n3:24491581
Subject Item
_:vb94664307
rdf:type
n2:Context
rdf:value
MMPIs partially preserved BBB integrity by preventing ECM protein degradation [>>132<<, 167]. In a PM mouse model, TNF484 reduced neuroinflammation, thereby improving survival in animals without antibiotic therapy [170]. Notably, there are remarkable differences in different mouse and rat strains in terms of BBB breakdown
n2:mentions
n3:15145598
Subject Item
_:vb94664308
rdf:type
n2:Context
rdf:value
MMPIs partially preserved BBB integrity by preventing ECM protein degradation [132, >>167<<]. In a PM mouse model, TNF484 reduced neuroinflammation, thereby improving survival in animals without antibiotic therapy [170]. Notably, there are remarkable differences in different mouse and rat strains in terms of BBB breakdown
n2:mentions
n3:24491581
Subject Item
_:vb94664309
rdf:type
n2:Context
rdf:value
In a PM mouse model, TNF484 reduced neuroinflammation, thereby improving survival in animals without antibiotic therapy [>>170<<]. Notably, there are remarkable differences in different mouse and rat strains in terms of BBB breakdown prevention by metalloproteinase inhibitors after LPS-induced neuroinflammation [171].
n2:mentions
n3:17428319
Subject Item
_:vb94664310
rdf:type
n2:Context
rdf:value
Notably, there are remarkable differences in different mouse and rat strains in terms of BBB breakdown prevention by metalloproteinase inhibitors after LPS-induced neuroinflammation [>>171<<].
n2:mentions
n3:17184743
Subject Item
_:vb94664311
rdf:type
n2:Context
rdf:value
As a consequence of bacterial meningitis and its associated inflammatory reaction, cerebrovascular complications are frequently observed in patients [>>124<<]. Focal ischemia caused by vasculitis results in cortical necrosis during meningitis [116, 124].
n2:mentions
n3:15509818
Subject Item
_:vb94664312
rdf:type
n2:Context
rdf:value
Focal ischemia caused by vasculitis results in cortical necrosis during meningitis [>>116<<, 124]. Breakdown of the BBB during the excessive neuroinflammatory reaction is a crucial step in the development of cerebral ischemia [116]. Since metalloproteinases are central regulators of BBB breakdown during bacterial meningitis
n2:mentions
n3:21734248
Subject Item
_:vb94664313
rdf:type
n2:Context
rdf:value
Focal ischemia caused by vasculitis results in cortical necrosis during meningitis [116, >>124<<]. Breakdown of the BBB during the excessive neuroinflammatory reaction is a crucial step in the development of cerebral ischemia [116]. Since metalloproteinases are central regulators of BBB breakdown during bacterial meningitis
n2:mentions
n3:15509818
Subject Item
_:vb94664314
rdf:type
n2:Context
rdf:value
Breakdown of the BBB during the excessive neuroinflammatory reaction is a crucial step in the development of cerebral ischemia [>>116<<]. Since metalloproteinases are central regulators of BBB breakdown during bacterial meningitis (discussed above), their inhibition during the acute disease is a valuable therapeutic strategy to reduce cortical necrosis. Pre-treatment or
n2:mentions
n3:21734248
Subject Item
_:vb94664315
rdf:type
n2:Context
rdf:value
Pre-treatment or treatment early in the course of disease with MMPIs is associated with reduced cortical necrosis in pneumococcal meningitis [>>128<<, 132, 167, 168, 172, 173] and with lower rates of intracerebral hemorrhage in meningococcal meningitis [169].
n2:mentions
n3:10639424
Subject Item
_:vb94664316
rdf:type
n2:Context
rdf:value
Pre-treatment or treatment early in the course of disease with MMPIs is associated with reduced cortical necrosis in pneumococcal meningitis [128, >>132<<, 167, 168, 172, 173] and with lower rates of intracerebral hemorrhage in meningococcal meningitis [169].
n2:mentions
n3:15145598
Subject Item
_:vb94664317
rdf:type
n2:Context
rdf:value
Pre-treatment or treatment early in the course of disease with MMPIs is associated with reduced cortical necrosis in pneumococcal meningitis [128, 132, >>167<<, 168, 172, 173] and with lower rates of intracerebral hemorrhage in meningococcal meningitis [169].
n2:mentions
n3:24491581
Subject Item
_:vb94664318
rdf:type
n2:Context
rdf:value
Pre-treatment or treatment early in the course of disease with MMPIs is associated with reduced cortical necrosis in pneumococcal meningitis [128, 132, 167, 168, >>172<<, 173] and with lower rates of intracerebral hemorrhage in meningococcal meningitis [169].
n2:mentions
n3:9778257
Subject Item
_:vb94664319
rdf:type
n2:Context
rdf:value
Pre-treatment or treatment early in the course of disease with MMPIs is associated with reduced cortical necrosis in pneumococcal meningitis [128, 132, 167, 168, 172, >>173<<] and with lower rates of intracerebral hemorrhage in meningococcal meningitis [169].
n2:mentions
n3:16790761
Subject Item
_:vb94664320
rdf:type
n2:Context
rdf:value
or treatment early in the course of disease with MMPIs is associated with reduced cortical necrosis in pneumococcal meningitis [128, 132, 167, 168, 172, 173] and with lower rates of intracerebral hemorrhage in meningococcal meningitis [>>169<<]. This neuroprotective effect is, however, reduced when the application of the inhibitors is delayed until the time of antibiotic therapy at the first appearance of disease symptoms [127, 174].
n2:mentions
n3:25551808
Subject Item
_:vb94664321
rdf:type
n2:Context
rdf:value
This neuroprotective effect is, however, reduced when the application of the inhibitors is delayed until the time of antibiotic therapy at the first appearance of disease symptoms [>>127<<, 174]. The early inhibition of MMPs during bacterial meningitis might be responsible for an overall reduction of the neuroinflammatory reaction with reduced BBB breakdown and cytokine production, thereby limiting the pathophysiological
n2:mentions
n3:11522576
Subject Item
_:vb94664322
rdf:type
n2:Context
rdf:value
MMPs during bacterial meningitis might be responsible for an overall reduction of the neuroinflammatory reaction with reduced BBB breakdown and cytokine production, thereby limiting the pathophysiological consequences of the disease [>>116<<].
n2:mentions
n3:21734248
Subject Item
_:vb94664323
rdf:type
n2:Context
rdf:value
Apoptosis of immature neurons in the dentate gyrus of the hippocampus during bacterial meningitis is caused by bacterial toxins, but also by an excessive inflammatory reaction from the host [105, >>116<<–118]. Several metalloproteinase inhibitors that inhibit ADAM17 (i.e., BB1001, Ro 32-7315) were found to prevent hippocampal apoptosis [127, 167].
n2:mentions
n3:21734248 n3:15529270 n3:12677451
Subject Item
_:vb94664324
rdf:type
n2:Context
rdf:value
Several metalloproteinase inhibitors that inhibit ADAM17 (i.e., BB1001, Ro 32-7315) were found to prevent hippocampal apoptosis [>>127<<, 167]. However, other ADAM17 inhibitors were unable to prevent neural cell death in the hippocampus [132]. On the other hand, Trocade—without having a specific ADAM17-inhibitory profile—successfully prevented hippocampal apoptosis [167,
n2:mentions
n3:11522576
Subject Item
_:vb94664325
rdf:type
n2:Context
rdf:value
Several metalloproteinase inhibitors that inhibit ADAM17 (i.e., BB1001, Ro 32-7315) were found to prevent hippocampal apoptosis [127, >>167<<]. However, other ADAM17 inhibitors were unable to prevent neural cell death in the hippocampus [132]. On the other hand, Trocade—without having a specific ADAM17-inhibitory profile—successfully prevented hippocampal apoptosis [167, 174].
n2:mentions
n3:24491581
Subject Item
_:vb94664326
rdf:type
n2:Context
rdf:value
However, other ADAM17 inhibitors were unable to prevent neural cell death in the hippocampus [>>132<<]. On the other hand, Trocade—without having a specific ADAM17-inhibitory profile—successfully prevented hippocampal apoptosis [167, 174]. As MMP-9 is directly involved in hippocampal cell death via the degradation of laminin [136, 137],
n2:mentions
n3:15145598
Subject Item
_:vb94664327
rdf:type
n2:Context
rdf:value
On the other hand, Trocade—without having a specific ADAM17-inhibitory profile—successfully prevented hippocampal apoptosis [>>167<<, 174]. As MMP-9 is directly involved in hippocampal cell death via the degradation of laminin [136, 137], inhibition of MMP-9—rather than ADAM17—might explain this neuroprotective effect of Trocade during bacterial meningitis. The
n2:mentions
n3:24491581
Subject Item
_:vb94664328
rdf:type
n2:Context
rdf:value
As MMP-9 is directly involved in hippocampal cell death via the degradation of laminin [>>136<<, 137], inhibition of MMP-9—rather than ADAM17—might explain this neuroprotective effect of Trocade during bacterial meningitis.
n2:mentions
n3:16000631
Subject Item
_:vb94664329
rdf:type
n2:Context
rdf:value
As MMP-9 is directly involved in hippocampal cell death via the degradation of laminin [136, >>137<<], inhibition of MMP-9—rather than ADAM17—might explain this neuroprotective effect of Trocade during bacterial meningitis.
n2:mentions
n3:20033829
Subject Item
_:vb94664330
rdf:type
n2:Context
rdf:value
The protective effect on hippocampal neurons is lower—but still present—when BB1001 or Trocade therapy is initiated together with antibiotics at time of symptom onset [>>127<<, 167, 174].
n2:mentions
n3:11522576
Subject Item
_:vb94664331
rdf:type
n2:Context
rdf:value
The protective effect on hippocampal neurons is lower—but still present—when BB1001 or Trocade therapy is initiated together with antibiotics at time of symptom onset [127, >>167<<, 174].
n2:mentions
n3:24491581
Subject Item
_:vb94664332
rdf:type
n2:Context
rdf:value
Apoptosis of dentate gyrus granular cell progenitors found in the hippocampus of humans [>>114<<] and animal models with bacterial meningitis [175, 176] correlates with behavioural and learning deficits [110–113], with increased hippocampal apoptosis being associated with impaired learning and memory performance in rat PM [111, 113].
n2:mentions
n3:10197818
Subject Item
_:vb94664333
rdf:type
n2:Context
rdf:value
Apoptosis of dentate gyrus granular cell progenitors found in the hippocampus of humans [114] and animal models with bacterial meningitis [>>175<<, 176] correlates with behavioural and learning deficits [110–113], with increased hippocampal apoptosis being associated with impaired learning and memory performance in rat PM [111, 113].
n2:mentions
n3:17938941
Subject Item
_:vb94664334
rdf:type
n2:Context
rdf:value
Apoptosis of dentate gyrus granular cell progenitors found in the hippocampus of humans [114] and animal models with bacterial meningitis [175, >>176<<] correlates with behavioural and learning deficits [110–113], with increased hippocampal apoptosis being associated with impaired learning and memory performance in rat PM [111, 113].
n2:mentions
n3:12836917
Subject Item
_:vb94664335
rdf:type
n2:Context
rdf:value
Apoptosis of dentate gyrus granular cell progenitors found in the hippocampus of humans [114] and animal models with bacterial meningitis [175, 176] correlates with behavioural and learning deficits [>>110<<–113], with increased hippocampal apoptosis being associated with impaired learning and memory performance in rat PM [111, 113].
n2:mentions
n3:12788989 n3:11110643 n3:11801337 n3:11109000
Subject Item
_:vb94664336
rdf:type
n2:Context
rdf:value
[114] and animal models with bacterial meningitis [175, 176] correlates with behavioural and learning deficits [110–113], with increased hippocampal apoptosis being associated with impaired learning and memory performance in rat PM [>>111<<, 113]. Protection from hippocampal apoptosis by BB1001 improved learning performance in rats with PM [127].
n2:mentions
n3:11110643
Subject Item
_:vb94664337
rdf:type
n2:Context
rdf:value
and animal models with bacterial meningitis [175, 176] correlates with behavioural and learning deficits [110–113], with increased hippocampal apoptosis being associated with impaired learning and memory performance in rat PM [111, >>113<<]. Protection from hippocampal apoptosis by BB1001 improved learning performance in rats with PM [127].
n2:mentions
n3:12788989
Subject Item
_:vb94664338
rdf:type
n2:Context
rdf:value
Protection from hippocampal apoptosis by BB1001 improved learning performance in rats with PM [>>127<<]. Similarly, in PM-infected rats treated with Trocade plus daptomycin, the observed reduction in hippocampal apoptosis was associated with a significant improvement of learning and memory function [174]. GM6001 therapy significantly
n2:mentions
n3:11522576
Subject Item
_:vb94664339
rdf:type
n2:Context
rdf:value
GM6001 therapy significantly protected hippocampal neurons and prevented PM-induced learning and memory impairments in neonatal rats [>>177<<]. Notably, all three therapies also significantly protected from cortical necrosis [127, 174, 177], which might also positively influence learning and memory performance after PM. Correspondingly, in adult rats, MMP-2 and -9 inhibition
n2:mentions
n3:25576979
Subject Item
_:vb94664340
rdf:type
n2:Context
rdf:value
Notably, all three therapies also significantly protected from cortical necrosis [>>127<<, 174, 177], which might also positively influence learning and memory performance after PM.
n2:mentions
n3:11522576
Subject Item
_:vb94664341
rdf:type
n2:Context
rdf:value
Notably, all three therapies also significantly protected from cortical necrosis [127, 174, >>177<<], which might also positively influence learning and memory performance after PM.
n2:mentions
n3:25576979
Subject Item
_:vb94664342
rdf:type
n2:Context
rdf:value
Correspondingly, in adult rats, MMP-2 and -9 inhibition further prevented cognitive impairment after PM possibly due to the observed successful preservation of BBB integrity during acute infection [>>178<<].
n2:mentions
n3:24419461
Subject Item
_:vb94664343
rdf:type
n2:Context
rdf:value
Bacterial meningitis induces sensorineural hearing loss by damaging hair cells and spiral ganglion neurons in the inner ear [>>122<<, 123]. In PM, CSF levels of TNF-α during acute infection are positively correlated with increased hearing threshold after infection [122].
n2:mentions
n3:27445150
Subject Item
_:vb94664344
rdf:type
n2:Context
rdf:value
Bacterial meningitis induces sensorineural hearing loss by damaging hair cells and spiral ganglion neurons in the inner ear [122, >>123<<]. In PM, CSF levels of TNF-α during acute infection are positively correlated with increased hearing threshold after infection [122].
n2:mentions
n3:12744466
Subject Item
_:vb94664345
rdf:type
n2:Context
rdf:value
In PM, CSF levels of TNF-α during acute infection are positively correlated with increased hearing threshold after infection [>>122<<]. Treatment with doxycycline or Trocade plus daptomycin significantly reduces CSF levels of TNF-α and other pro-inflammatory cytokines and significantly improves hearing thresholds after PM [173, 174]. Doxycycline—with its broad spectrum
n2:mentions
n3:27445150
Subject Item
_:vb94664346
rdf:type
n2:Context
rdf:value
Treatment with doxycycline or Trocade plus daptomycin significantly reduces CSF levels of TNF-α and other pro-inflammatory cytokines and significantly improves hearing thresholds after PM [>>173<<, 174]. Doxycycline—with its broad spectrum MMP inhibition profile—preserves spiral ganglion neurons from PM-induced cell death [173]. The overall reduction of neuroinflammation in both therapies might be attributable to a reduced
n2:mentions
n3:16790761
Subject Item
_:vb94664347
rdf:type
n2:Context
rdf:value
Doxycycline—with its broad spectrum MMP inhibition profile—preserves spiral ganglion neurons from PM-induced cell death [>>173<<]. The overall reduction of neuroinflammation in both therapies might be attributable to a reduced concentration of ototoxic compounds in the cochlear duct, thereby preventing ototoxic damage in spiral ganglion neurons and hair cells of
n2:mentions
n3:16790761
Subject Item
_:vb94664348
rdf:type
n2:Context
rdf:value
Two metalloproteinase inhibitors—Ro 32-7315 and high-dose TNF484, both with high specificity for ADAM17—were reported to increase mortality during acute bacterial meningitis when administrated early after infection [>>132<<, 167]. In an experimental model of PM with TNF-α-deficient mice, mortality was significantly increased despite treatment with antibiotics, indicating that TNF-α may play an essential role during infection and inflammation, being necessary
n2:mentions
n3:15145598
Subject Item
_:vb94664349
rdf:type
n2:Context
rdf:value
Two metalloproteinase inhibitors—Ro 32-7315 and high-dose TNF484, both with high specificity for ADAM17—were reported to increase mortality during acute bacterial meningitis when administrated early after infection [132, >>167<<]. In an experimental model of PM with TNF-α-deficient mice, mortality was significantly increased despite treatment with antibiotics, indicating that TNF-α may play an essential role during infection and inflammation, being necessary for
n2:mentions
n3:24491581
Subject Item
_:vb94664350
rdf:type
n2:Context
rdf:value
mice, mortality was significantly increased despite treatment with antibiotics, indicating that TNF-α may play an essential role during infection and inflammation, being necessary for host defense in the early stages of infection [>>179<<]. In PM, TNF-α inhibition by very potent ADAM17 inhibitors might, therefore, be rather detrimental than beneficial despite being neuroprotective in survivors, especially when applied at a time when TNF-α is a major contributor of the
n2:mentions
n3:15207270
Subject Item
_:vb94664351
rdf:type
n5:Section
dc:title
matrix metalloproteinases in multiple sclerosis
n5:contains
_:vb94664376 _:vb94664377 _:vb94664378 _:vb94664379 _:vb94664380 _:vb94664381 _:vb94664382 _:vb94664383 _:vb94664368 _:vb94664369 _:vb94664370 _:vb94664371 _:vb94664372 _:vb94664373 _:vb94664374 _:vb94664375 _:vb94664360 _:vb94664361 _:vb94664362 _:vb94664363 _:vb94664364 _:vb94664365 _:vb94664366 _:vb94664367 _:vb94664352 _:vb94664353 _:vb94664354 _:vb94664355 _:vb94664356 _:vb94664357 _:vb94664358 _:vb94664359 _:vb94664392 _:vb94664393 _:vb94664394 _:vb94664395 _:vb94664384 _:vb94664385 _:vb94664386 _:vb94664387 _:vb94664388 _:vb94664389 _:vb94664390 _:vb94664391
Subject Item
_:vb94664352
rdf:type
n2:Context
rdf:value
Multiple sclerosis (MS) is a chronic autoimmune disease of the CNS, leading to progressive deterioration of motor, sensory, vegetative and cognitive functions [>>180<<, 181]. The pathogenesis of MS encompasses both features of acute and subacute inflammation, and of chronic neurodegeneration, mainly as a result of the former.
n2:mentions
n3:29576504
Subject Item
_:vb94664353
rdf:type
n2:Context
rdf:value
Multiple sclerosis (MS) is a chronic autoimmune disease of the CNS, leading to progressive deterioration of motor, sensory, vegetative and cognitive functions [180, >>181<<]. The pathogenesis of MS encompasses both features of acute and subacute inflammation, and of chronic neurodegeneration, mainly as a result of the former.
n2:mentions
n3:30300457
Subject Item
_:vb94664354
rdf:type
n2:Context
rdf:value
There are more than 2.3 million patients worldwide, making MS the most important neurological diseases of young adulthood [>>180<<]. The disease affects predominantly Caucasians with highest prevalence in populations of Northern European origin.
n2:mentions
n3:29576504
Subject Item
_:vb94664355
rdf:type
n2:Context
rdf:value
while there is strong evidence for an interplay of genetic and environmental factors (smoking, lack of sun exposure/vitamin D deficiency, Epstein–Barr virus (EBV) infection) responsible for susceptibility and course of disease [>>180<<, 181]. The classical understanding of MS pathogenesis is based on three essential paradigms.
n2:mentions
n3:29576504
Subject Item
_:vb94664356
rdf:type
n2:Context
rdf:value
while there is strong evidence for an interplay of genetic and environmental factors (smoking, lack of sun exposure/vitamin D deficiency, Epstein–Barr virus (EBV) infection) responsible for susceptibility and course of disease [180, >>181<<]. The classical understanding of MS pathogenesis is based on three essential paradigms.
n2:mentions
n3:30300457
Subject Item
_:vb94664357
rdf:type
n2:Context
rdf:value
Demyelination is not restricted to white matter, but extends steadily into the grey matter in the course of disease [>>182<<]. Neuronal loss as the cellular substrate of disability worsening occurs in the course of demyelination, but to an even larger extent outside and independent of focal demyelination. Additionally, it seems that a relevant fraction of
n2:mentions
n3:16230320
Subject Item
_:vb94664358
rdf:type
n2:Context
rdf:value
Additionally, it seems that a relevant fraction of patients have a form of MS where no white matter demyelination occurs [>>183<<]. Further, the phenotypic characterization of MS subtypes is not based on distinct molecular mechanisms. According to the current understanding, there is a continuum of several pathogenetic pathways, which may predominate at certain
n2:mentions
n3:30143361
Subject Item
_:vb94664359
rdf:type
n2:Context
rdf:value
According to the current understanding, there is a continuum of several pathogenetic pathways, which may predominate at certain stages and disease duration [>>180<<]. Lastly, the success of B-cell targeting therapies has revolutionized our understanding on the autoimmune response in MS: B cells seem to orchestrate and drive the disease directly and indirectly via T cells and other cells in acute and
n2:mentions
n3:29576504
Subject Item
_:vb94664360
rdf:type
n2:Context
rdf:value
of B-cell targeting therapies has revolutionized our understanding on the autoimmune response in MS: B cells seem to orchestrate and drive the disease directly and indirectly via T cells and other cells in acute and progressive phases [>>184<<].
n2:mentions
n3:29244240
Subject Item
_:vb94664361
rdf:type
n2:Context
rdf:value
Leukocytes, as well as cells that form the BBB (endothelial cells, astrocytes), produce MMPs and TIMPs, and BBB leakage is a result of MMP upregulation that is not any more compensated by TIMP activity [>>185<<]. Basal membrane type IV collagen as the primary barrier structure at the BBB is a main substrate for gelatinases (MMP-2 and -9), which makes them specific effector molecules of leukocyte extravasation into the brain parenchyma. In MS
n2:mentions
n3:10534241
Subject Item
_:vb94664362
rdf:type
n2:Context
rdf:value
In MS lesions, upregulation of MMP-1, -2, -3, -7 and -9 was demonstrated by immunohistochemistry [>>186<<–188] and on the transcriptional level [189], and correlated with inflammatory activity in lesions.
n2:mentions
n3:8786388 n3:9444361 n3:9364466
Subject Item
_:vb94664363
rdf:type
n2:Context
rdf:value
In MS lesions, upregulation of MMP-1, -2, -3, -7 and -9 was demonstrated by immunohistochemistry [186–188] and on the transcriptional level [>>189<<], and correlated with inflammatory activity in lesions.
n2:mentions
n3:11522577
Subject Item
_:vb94664364
rdf:type
n2:Context
rdf:value
In the experimental autoimmune encephalitis (EAE) model of MS, the upregulation of MMP-7 and -9 correlated with the course of disease severity [>>190<<]. In contrast, knockout mice deficient for MMP-9 were less susceptible to EAE induction [191].
n2:mentions
n3:9549496
Subject Item
_:vb94664365
rdf:type
n2:Context
rdf:value
In contrast, knockout mice deficient for MMP-9 were less susceptible to EAE induction [>>191<<]. In the delayed-type hypersensitivity (DTH) rat model, protein and transcriptional expression of several MMPs was increased. Moreover, microinjection of MMP-7, -8 and -9 into brain parenchyma led to demyelination and axonal damage, the
n2:mentions
n3:10587514
Subject Item
_:vb94664366
rdf:type
n2:Context
rdf:value
Axonal damage continued even when the integrity of the BBB was re-established [>>192<<, 193]. The fact that MMPs may cause direct neuronal damage is very important for the concept of clinical progression of MS. Their increased expression also in chronic phases of lesions development [189] may contribute to chronic
n2:mentions
n3:9670846
Subject Item
_:vb94664367
rdf:type
n2:Context
rdf:value
Axonal damage continued even when the integrity of the BBB was re-established [192, >>193<<]. The fact that MMPs may cause direct neuronal damage is very important for the concept of clinical progression of MS. Their increased expression also in chronic phases of lesions development [189] may contribute to chronic smouldering
n2:mentions
n3:11673322
Subject Item
_:vb94664368
rdf:type
n2:Context
rdf:value
Their increased expression also in chronic phases of lesions development [>>189<<] may contribute to chronic smouldering neuronal loss, and eventually lead to progressive deterioration of neurological functions.
n2:mentions
n3:11522577
Subject Item
_:vb94664369
rdf:type
n2:Context
rdf:value
Several groups have demonstrated an increase of MMP-9 in CSF [>>195<<, 196] and in blood of MS patients [185, 197]. The levels correlated with disease activity (higher in RRMS/SPMS vs PPMS [195], or MRI activity [185, 197].
n2:mentions
n3:9874483
Subject Item
_:vb94664370
rdf:type
n2:Context
rdf:value
Several groups have demonstrated an increase of MMP-9 in CSF [195, >>196<<] and in blood of MS patients [185, 197]. The levels correlated with disease activity (higher in RRMS/SPMS vs PPMS [195], or MRI activity [185, 197].
n2:mentions
n3:1334098
Subject Item
_:vb94664371
rdf:type
n2:Context
rdf:value
Several groups have demonstrated an increase of MMP-9 in CSF [195, 196] and in blood of MS patients [>>185<<, 197]. The levels correlated with disease activity (higher in RRMS/SPMS vs PPMS [195], or MRI activity [185, 197].
n2:mentions
n3:10534241
Subject Item
_:vb94664372
rdf:type
n2:Context
rdf:value
Several groups have demonstrated an increase of MMP-9 in CSF [195, 196] and in blood of MS patients [185, >>197<<]. The levels correlated with disease activity (higher in RRMS/SPMS vs PPMS [195], or MRI activity [185, 197].
n2:mentions
n3:10071048
Subject Item
_:vb94664373
rdf:type
n2:Context
rdf:value
The levels correlated with disease activity (higher in RRMS/SPMS vs PPMS [>>195<<], or MRI activity [185, 197].
n2:mentions
n3:9874483
Subject Item
_:vb94664374
rdf:type
n2:Context
rdf:value
The levels correlated with disease activity (higher in RRMS/SPMS vs PPMS [195], or MRI activity [>>185<<, 197]. In a longitudinal study of SPMS patients, the increase of MMP-9/TIMP-1 ratio preceded the occurrence of new gadolinium-enhancing lesions [198]. This study showed also higher median levels of TIMP-1. MMP-9 trended lower in patients
n2:mentions
n3:10534241
Subject Item
_:vb94664375
rdf:type
n2:Context
rdf:value
The levels correlated with disease activity (higher in RRMS/SPMS vs PPMS [195], or MRI activity [185, >>197<<]. In a longitudinal study of SPMS patients, the increase of MMP-9/TIMP-1 ratio preceded the occurrence of new gadolinium-enhancing lesions [198]. This study showed also higher median levels of TIMP-1. MMP-9 trended lower in patients
n2:mentions
n3:10071048
Subject Item
_:vb94664376
rdf:type
n2:Context
rdf:value
In a longitudinal study of SPMS patients, the increase of MMP-9/TIMP-1 ratio preceded the occurrence of new gadolinium-enhancing lesions [>>198<<]. This study showed also higher median levels of TIMP-1. MMP-9 trended lower in patients receiving IFNβ compared to placebo recipients. Similarly, steroids treatment used as interventional therapy during acute exacerbation of MS led to a
n2:mentions
n3:12525717
Subject Item
_:vb94664377
rdf:type
n2:Context
rdf:value
used as interventional therapy during acute exacerbation of MS led to a decrease of MMP-9 in CSF with the most prominent effect in patients with gadolinium-enhancing lesions, further supporting its functional role in BBB breakdown [>>199<<]. Moreover, quantitative PCR analysis revealed that IFNβ therapy downregulated the expression of MMP-2 and -9 in blood leukocytes.
n2:mentions
n3:8649561
Subject Item
_:vb94664378
rdf:type
n2:Context
rdf:value
Patients that developed neutralizing antibodies against IFNβ showed an increase of these MMPs in circulation, supporting the concept that these antibodies reduce the therapeutic efficacy IFNβ therapy [>>200<<].
n2:mentions
n3:14607790
Subject Item
_:vb94664379
rdf:type
n2:Context
rdf:value
Bar-Or et al. performed a comprehensive analysis of transcriptional expression of 23 MMPs by quantitative PCR in monocytes as well as in B and T cells from healthy controls and MS patients [>>201<<]. Each of these cell types had their specific pattern of enzymes across the involved members of the MMP family. A specific increase of MMP-2 and -14, and of TIMP-2 in monocytes of MS patients was observed. Kouwenhoven et al. found that
n2:mentions
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Kouwenhoven et al. found that mRNA levels of MMP-1, -3, -7, -9 and of TIMP-1 in monocytes were elevated in MS, while those of MMP-14 did not differ, as compared to controls [>>202<<]. These studies underline that molecular mechanisms of tissue degradation are not restricted to only MMP-9, but result from an interplay of many MMPs from many cellular sources. Nevertheless, while results from different investigators
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MMP-9 is involved in oligodendrocyte regrowth [>>203<<], while MMP-7 cleaves remyelination-impairing fibronectin to allow remyelination, and the authors speculate that a too low MMP-7 level contributes to the persistence of demyelination in chronic MS lesions and prevents oligodendrocyte
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cleaves remyelination-impairing fibronectin to allow remyelination, and the authors speculate that a too low MMP-7 level contributes to the persistence of demyelination in chronic MS lesions and prevents oligodendrocyte maturation [>>204<<]. A further function of MMPs for synaptogenesis has been recognized [205, 206]. These findings are relevant for the concept how MMP inhibition could be used as therapeutic approach in MS.
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A further function of MMPs for synaptogenesis has been recognized [>>205<<, 206]. These findings are relevant for the concept how MMP inhibition could be used as therapeutic approach in MS.
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A further function of MMPs for synaptogenesis has been recognized [205, >>206<<]. These findings are relevant for the concept how MMP inhibition could be used as therapeutic approach in MS.
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This was bolstered by the observation that current therapies such as IFNβ, or later natalizumab [>>207<<] downregulate MMPs as part of their mode of action.
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The hypothesis that the therapeutic effect of IFNβ may be mediated via its suppressive effect on MMP-9 expression in T cells was further corroborated by a reduction of their migration across an artificial BBB [>>208<<, 209].
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The hypothesis that the therapeutic effect of IFNβ may be mediated via its suppressive effect on MMP-9 expression in T cells was further corroborated by a reduction of their migration across an artificial BBB [208, >>209<<].
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A number of hydroxamic acid inhibitor type compounds, which inactivate the enzymatic activity of MMPs by binding to the catalytic zinc of MMPs, have led to disease severity attenuation in EAE [>>210<<–212]. Similarly, such compounds reduced the capacity of T cells to migrate across an in vitro BBB model [213].
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Similarly, such compounds reduced the capacity of T cells to migrate across an in vitro BBB model [>>213<<]. However, for several reasons clinical studies have never started. In oncology, the initially promising preclinical results with MMPIs were not confirmed in clinical trials. The same was the case in rheumatoid arthritis. Additionally,
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Additionally, depending on their enzymatic target profile, adverse events and specific signs of toxicity were recognized during chronic dosing, which precluded the intended long-term use as maintenance therapy in MS (for review see [>>214<<]). Evidence for the role of MMPs in tissue repair in subacute and stable phases of the disease suggests that long-term MMP inhibition could have detrimental effects.
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The intent to overcome this by targeting only ‘bad’ MMPs via hyper-selective substrate profiles fell short on the basis that tissue destruction and repair can be mediated by the very same MMPs (e.g., MMP-7 and -9) [>>204<<], depending on the acuity of disease at a given time point.
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Minocycline, a tetracycline antibiotic that exerts broad-spectrum inhibition of MMPs, demonstrated in two phase 2 studies in MS efficacy in reducing gadolinium-enhancing lesions [215, >>216<<], which encouraged the study group to execute a phase 3 clinical trial [217] with 142 patients with a first MS attack.
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antibiotic that exerts broad-spectrum inhibition of MMPs, demonstrated in two phase 2 studies in MS efficacy in reducing gadolinium-enhancing lesions [215, 216], which encouraged the study group to execute a phase 3 clinical trial [>>217<<] with 142 patients with a first MS attack.
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EMMPRIN (extracellular matrix metalloproteinase inducer, CD147) is a membrane glycoprotein of the immunoglobulin superfamily whose levels are reduced in T cells by minocycline [>>218<<]. Thus, minocycline treatment likely reduces the activity and secondarily the release and production of MMPs resulting in diminished leukocyte extravasation of leukocytes into the CNS. The Canadian study group that has run all minocycline
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Broad-spectrum MMPIs are the obvious drug candidates here, given the array of MMPs upregulated in this condition, as they have been shown to be free of side effects for a dosing period of several days [>>219<<]. Despite Health Authorities have defined the development path for the development of compounds for relapse therapy [220], the pharmaceutical industry has so far not engaged in such development activities. However, this may be an
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