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n3:pmcid
PMC0
bibo:doi
10.1007%2Fs11481-009-9164-4
n2:contains
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Subject Item
_:vb5759300
rdf:type
n2:Section
dc:title
initiation of a tissue immune response
n2:contains
_:vb5759316 _:vb5759317 _:vb5759318 _:vb5759319 _:vb5759312 _:vb5759313 _:vb5759314 _:vb5759315 _:vb5759324 _:vb5759325 _:vb5759326 _:vb5759320 _:vb5759321 _:vb5759322 _:vb5759323 _:vb5759301 _:vb5759302 _:vb5759303 _:vb5759308 _:vb5759309 _:vb5759310 _:vb5759311 _:vb5759304 _:vb5759305 _:vb5759306 _:vb5759307
Subject Item
_:vb5759301
rdf:type
n3:Context
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In the brain, the primary cells in the innate immune response are microglia, although astrocytes and neurons may also play an immune role (Streit and Kincaid-Colton >>1995<<). Like macrophages elsewhere in the body, microglia recognize pathogens via pattern recognition receptors (PRRs) that include specific toll-like receptors (TLRs), nucleotide-binding oligomerization domain (NOD) proteins, and non-TLR
n3:mentions
n4:7652527
Subject Item
_:vb5759302
rdf:type
n3:Context
rdf:value
membrane and cytosolic receptors interact with classes of pathogen-associated molecular patterns (PAMPs) or with damage-associated molecular patterns (DAMPs) in the environment to initiate cellular defense mechanisms (Han and Ulevitch >>2005<<; Rubartelli and Lotze 2007; Serhan and Levy 2003; Sterka and Marriott 2006). Downstream signaling events begin with engagement of adaptor proteins (e.g., MyD88, Trif, TRADD/TRAF) with surface pathogen receptors.
n3:mentions
n4:16369559
Subject Item
_:vb5759303
rdf:type
n3:Context
rdf:value
interact with classes of pathogen-associated molecular patterns (PAMPs) or with damage-associated molecular patterns (DAMPs) in the environment to initiate cellular defense mechanisms (Han and Ulevitch 2005; Rubartelli and Lotze >>2007<<; Serhan and Levy 2003; Sterka and Marriott 2006). Downstream signaling events begin with engagement of adaptor proteins (e.g., MyD88, Trif, TRADD/TRAF) with surface pathogen receptors.
n3:mentions
n4:17845865
Subject Item
_:vb5759304
rdf:type
n3:Context
rdf:value
of pathogen-associated molecular patterns (PAMPs) or with damage-associated molecular patterns (DAMPs) in the environment to initiate cellular defense mechanisms (Han and Ulevitch 2005; Rubartelli and Lotze 2007; Serhan and Levy >>2003<<; Sterka and Marriott 2006). Downstream signaling events begin with engagement of adaptor proteins (e.g., MyD88, Trif, TRADD/TRAF) with surface pathogen receptors.
n3:mentions
n4:12947982
Subject Item
_:vb5759305
rdf:type
n3:Context
rdf:value
molecular patterns (PAMPs) or with damage-associated molecular patterns (DAMPs) in the environment to initiate cellular defense mechanisms (Han and Ulevitch 2005; Rubartelli and Lotze 2007; Serhan and Levy 2003; Sterka and Marriott >>2006<<). Downstream signaling events begin with engagement of adaptor proteins (e.g., MyD88, Trif, TRADD/TRAF) with surface pathogen receptors.
n3:mentions
n4:16842862
Subject Item
_:vb5759306
rdf:type
n3:Context
rdf:value
This important macrophage state is characterized by involvement of interferon gamma (IFN-γ), a cytokine that coordinates induction signals by initiation of the “killing” phase of macrophage function (Adams and Hamilton >>1987<<). Well known in the periphery as a product of T cells, IFN-γ is most likely produced by microglia (and astrocytes) on immune stimulation with PAMPs (Suzuki et al. 2005) and is also a critical component of the brain’s innate immune
n3:mentions
n4:2957307
Subject Item
_:vb5759307
rdf:type
n3:Context
rdf:value
Well known in the periphery as a product of T cells, IFN-γ is most likely produced by microglia (and astrocytes) on immune stimulation with PAMPs (Suzuki et al. >>2005<<) and is also a critical component of the brain’s innate immune response.
n3:mentions
n4:15619519
Subject Item
_:vb5759308
rdf:type
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rdf:value
After infiltration into injury sites, these newly recruited macrophages phagocytose dead or dying immune cells (van Rossum et al. >>2008<<) then exit the tissue via the lymphatic system and are rapidly dispersed throughout the vasculature and eventually removed from circulation.
n3:mentions
n4:18069669
Subject Item
_:vb5759309
rdf:type
n3:Context
rdf:value
restriction of paracellular flux by endothelial cell tight junctions not only reduces solute transfer but also restricts movement of cells, such as circulating monocytes and lymphocytes, across the blood–brain barrier (Abbott et al. >>2006<<). Injury and disease, however, may alter blood–brain barrier function and increase peripheral cell invasion (Soulet and Rivest 2008).
n3:mentions
n4:16371949
Subject Item
_:vb5759310
rdf:type
n3:Context
rdf:value
Injury and disease, however, may alter blood–brain barrier function and increase peripheral cell invasion (Soulet and Rivest >>2008<<). Despite cerebral ischemia that is known to damage the blood–brain barrier, Denker et al. (2007) and Schilling et al. (2005) have independently shown that resident microglia and not infiltrating macrophages are the predominant cell type
n3:mentions
n4:18487084
Subject Item
_:vb5759311
rdf:type
n3:Context
rdf:value
Despite cerebral ischemia that is known to damage the blood–brain barrier, Denker et al. (>>2007<<) and Schilling et al. (2005) have independently shown that resident microglia and not infiltrating macrophages are the predominant cell type at the ischemic injury site.
n3:mentions
n4:17212701
Subject Item
_:vb5759312
rdf:type
n3:Context
rdf:value
Despite cerebral ischemia that is known to damage the blood–brain barrier, Denker et al. (2007) and Schilling et al. (>>2005<<) have independently shown that resident microglia and not infiltrating macrophages are the predominant cell type at the ischemic injury site.
n3:mentions
n4:16153641
Subject Item
_:vb5759313
rdf:type
n3:Context
rdf:value
Other entry sites for blood-borne cells such as the choroid plexus, however, may also be a factor during brain injury (Reboldi et al. >>2009<<). One point of caution, recent studies by Mildner et al. (2007) and Ajami et al. (2007) have shown that the techniques commonly used to study this phenomenon can be flawed, making interpretation of disparate data more difficult. More
n3:mentions
n4:19305396
Subject Item
_:vb5759314
rdf:type
n3:Context
rdf:value
One point of caution, recent studies by Mildner et al. (>>2007<<) and Ajami et al. (2007) have shown that the techniques commonly used to study this phenomenon can be flawed, making interpretation of disparate data more difficult.
n3:mentions
n4:18026096
Subject Item
_:vb5759315
rdf:type
n3:Context
rdf:value
One point of caution, recent studies by Mildner et al. (2007) and Ajami et al. (>>2007<<) have shown that the techniques commonly used to study this phenomenon can be flawed, making interpretation of disparate data more difficult.
n3:mentions
n4:18026097
Subject Item
_:vb5759316
rdf:type
n3:Context
rdf:value
More detail on this highly controversial area of research is provided in several excellent reviews (Pachter et al. >>2003<<; Soulet and Rivest 2008; Villoslada et al. 2008; Schwartz et al. 2009).
n3:mentions
n4:12834104
Subject Item
_:vb5759317
rdf:type
n3:Context
rdf:value
More detail on this highly controversial area of research is provided in several excellent reviews (Pachter et al. 2003; Soulet and Rivest >>2008<<; Villoslada et al. 2008; Schwartz et al. 2009).
n3:mentions
n4:18487084
Subject Item
_:vb5759318
rdf:type
n3:Context
rdf:value
More detail on this highly controversial area of research is provided in several excellent reviews (Pachter et al. 2003; Soulet and Rivest 2008; Villoslada et al. >>2008<<; Schwartz et al. 2009).
n3:mentions
n4:18534912
Subject Item
_:vb5759319
rdf:type
n3:Context
rdf:value
More detail on this highly controversial area of research is provided in several excellent reviews (Pachter et al. 2003; Soulet and Rivest 2008; Villoslada et al. 2008; Schwartz et al. >>2009<<). Table
n3:mentions
n4:19103265
Subject Item
_:vb5759320
rdf:type
n3:Context
rdf:value
The brain not only lacks a defined lymphatic system but has very low levels of protein in the interstitial fluid, thus limiting fluid movement into the brain (Abbott >>2004<<; Boulton et al. 1998; Weller et al. 2008).
n3:mentions
n4:15186921
Subject Item
_:vb5759321
rdf:type
n3:Context
rdf:value
The brain not only lacks a defined lymphatic system but has very low levels of protein in the interstitial fluid, thus limiting fluid movement into the brain (Abbott 2004; Boulton et al. >>1998<<; Weller et al. 2008).
n3:mentions
n4:9458903
Subject Item
_:vb5759322
rdf:type
n3:Context
rdf:value
The brain not only lacks a defined lymphatic system but has very low levels of protein in the interstitial fluid, thus limiting fluid movement into the brain (Abbott 2004; Boulton et al. 1998; Weller et al. >>2008<<). Drainage of some brain interstitial fluid does occur in the perivascular spaces between blood vessel walls and brain parenchyma (Carare et al. 2008; Weller et al. 2008). This drainage depends on cardiac output and allows fluid to exit
n3:mentions
n4:18363936
Subject Item
_:vb5759323
rdf:type
n3:Context
rdf:value
Drainage of some brain interstitial fluid does occur in the perivascular spaces between blood vessel walls and brain parenchyma (Carare et al. >>2008<<; Weller et al. 2008).
n3:mentions
n4:18208483
Subject Item
_:vb5759324
rdf:type
n3:Context
rdf:value
Drainage of some brain interstitial fluid does occur in the perivascular spaces between blood vessel walls and brain parenchyma (Carare et al. 2008; Weller et al. >>2008<<). This drainage depends on cardiac output and allows fluid to exit the brain along the surface of the basement membranes of the arterial system. Proteins injected into the cerebral spinal fluid (CSF) of the lateral ventricles also find
n3:mentions
n4:18363936
Subject Item
_:vb5759325
rdf:type
n3:Context
rdf:value
Boulton et al. (>>1996<<) have shown that ligating cervical and thoracic lymph nodes reduced appearance of the protein tracer in the blood.
n3:mentions
n4:8875467
Subject Item
_:vb5759326
rdf:type
n3:Context
rdf:value
While soluble proteins may enter circulating blood via this system, removal of macrophagic cells from the brain is unlikely (Carare et al. >>2008<<). Thus, reducing proinflammatory microglia by apoptosis and engulfment via newly recruited monocytes are unlikely to be important mechanisms for inactivating the innate immune response in the brain.
n3:mentions
n4:18208483
Subject Item
_:vb5759327
rdf:type
n2:Section
dc:title
downregulation of classical activation: feedback reduction of signaling pathways
n2:contains
_:vb5759344 _:vb5759345 _:vb5759346 _:vb5759347 _:vb5759348 _:vb5759349 _:vb5759336 _:vb5759337 _:vb5759338 _:vb5759339 _:vb5759340 _:vb5759341 _:vb5759342 _:vb5759343 _:vb5759328 _:vb5759329 _:vb5759330 _:vb5759331 _:vb5759332 _:vb5759333 _:vb5759334 _:vb5759335
Subject Item
_:vb5759328
rdf:type
n3:Context
rdf:value
In some cases, these regulatory proteins are made when the surface pattern recognition receptors are activated, or they may be constitutively expressed in the immune cell (Han and Ulevitch >>2005<<; Serhan and Levy 2003; Ulevitch et al. 2004).
n3:mentions
n4:16369559
Subject Item
_:vb5759329
rdf:type
n3:Context
rdf:value
In some cases, these regulatory proteins are made when the surface pattern recognition receptors are activated, or they may be constitutively expressed in the immune cell (Han and Ulevitch 2005; Serhan and Levy >>2003<<; Ulevitch et al. 2004).
n3:mentions
n4:12947982
Subject Item
_:vb5759330
rdf:type
n3:Context
rdf:value
In some cases, these regulatory proteins are made when the surface pattern recognition receptors are activated, or they may be constitutively expressed in the immune cell (Han and Ulevitch 2005; Serhan and Levy 2003; Ulevitch et al. >>2004<<). For example, production of TRIAD3, which mediates ubiquitination and subsequent degradation of TLRs, reduces TLR levels on surface membranes (Chuang and Ulevitch 2004).
n3:mentions
n4:15576198
Subject Item
_:vb5759331
rdf:type
n3:Context
rdf:value
For example, production of TRIAD3, which mediates ubiquitination and subsequent degradation of TLRs, reduces TLR levels on surface membranes (Chuang and Ulevitch >>2004<<). Responsiveness of the immune cell to pathogens drops accordingly. Competition between functional and nonfunctional adaptor proteins such as MyD88 and a splice variant of MyD88 (MyD88s) has been shown to reduce TLR signaling, while
n3:mentions
n4:15107846
Subject Item
_:vb5759332
rdf:type
n3:Context
rdf:value
of MyD88 (MyD88s) has been shown to reduce TLR signaling, while adaptor proteins such as Toll inhibitor protein, which sequester a corresponding signaling protein, also downregulate proinflammatory signaling pathways (Zhang and Ghosh >>2002<<). Suppressor of cytokine signaling proteins is an additional family of regulatory proteins that depress the IFN-γ activation pathway at multiple points (see review by Baetz et al. 2004).
n3:mentions
n4:11751856
Subject Item
_:vb5759333
rdf:type
n3:Context
rdf:value
Suppressor of cytokine signaling proteins is an additional family of regulatory proteins that depress the IFN-γ activation pathway at multiple points (see review by Baetz et al. >>2004<<). Interestingly, CD45, a marker commonly used to identify “activated” microglia in the brain, is a protein tyrosine phosphatase that inhibits JAK family kinases (Townsend et al. 2004). Activation of the CD45 phosphatase by cross-linking
n3:mentions
n4:15491991
Subject Item
_:vb5759334
rdf:type
n3:Context
rdf:value
Interestingly, CD45, a marker commonly used to identify “activated” microglia in the brain, is a protein tyrosine phosphatase that inhibits JAK family kinases (Townsend et al. >>2004<<). Activation of the CD45 phosphatase by cross-linking with an anti-CD45 antibody reduces lipopolysaccharide (LPS)-mediated proinflammatory signaling in microglia (Tan et al. 2000). However, studies with CD45 knockout mice have revealed
n3:mentions
n4:15147773
Subject Item
_:vb5759335
rdf:type
n3:Context
rdf:value
Activation of the CD45 phosphatase by cross-linking with an anti-CD45 antibody reduces lipopolysaccharide (LPS)-mediated proinflammatory signaling in microglia (Tan et al. >>2000<<). However, studies with CD45 knockout mice have revealed more complex actions of the tyrosine phosphatase that may include sustaining inflammation under some circumstances by “resetting” kinases via removal of phosphate groups (Abbas et
n3:mentions
n4:11027218
Subject Item
_:vb5759336
rdf:type
n3:Context
rdf:value
studies with CD45 knockout mice have revealed more complex actions of the tyrosine phosphatase that may include sustaining inflammation under some circumstances by “resetting” kinases via removal of phosphate groups (Abbas et al. >>2002<<).
n3:mentions
n4:12020956
Subject Item
_:vb5759337
rdf:type
n3:Context
rdf:value
Recently, noncoding RNA oligonucleotides (microRNA or miRNA) have been shown to regulate gene expression by binding to 3′ untranslated regions of specific target genes (Tili et al. >>2007<<; Valencia-Sanchez et al. 2006). Microarray analysis has detected significantly increased expression of at least three miRNAs when macrophages are stimulated with TNF-α, Poly I:
n3:mentions
n4:17911593
Subject Item
_:vb5759338
rdf:type
n3:Context
rdf:value
Recently, noncoding RNA oligonucleotides (microRNA or miRNA) have been shown to regulate gene expression by binding to 3′ untranslated regions of specific target genes (Tili et al. 2007; Valencia-Sanchez et al. >>2006<<). Microarray analysis has detected significantly increased expression of at least three miRNAs when macrophages are stimulated with TNF-α, Poly I:
n3:mentions
n4:16510870
Subject Item
_:vb5759339
rdf:type
n3:Context
rdf:value
Microarray analysis has detected significantly increased expression of at least three miRNAs when macrophages are stimulated with TNF-α, Poly I:C, or LPS (O’Connell et al. >>2007<<). One of these, miR 146, has been shown to reduce expression of TRAF6 and other proteins involved in nuclear factor (NF)-κB signaling and to reduce the production and release of NF-κB -regulated cytokines. Though their mechanism of action
n3:mentions
n4:17242365
Subject Item
_:vb5759340
rdf:type
n3:Context
rdf:value
Though their mechanism of action is not yet clear, miRNAs provide an interesting means to alter the extent and timing of the proinflammatory phase of the innate immune response (Tili et al. >>2007<<).
n3:mentions
n4:17911593
Subject Item
_:vb5759341
rdf:type
n3:Context
rdf:value
In macrophages, exposure to LPS or IL-1 upregulates levels of IL-1RII, a nonfunctional receptor for IL-1α and IL-1β that binds IL-1 but fails to trigger intracellular signaling (Han and Ulevitch >>2005<<;Pousset et al. 2001).
n3:mentions
n4:16369559
Subject Item
_:vb5759342
rdf:type
n3:Context
rdf:value
In macrophages, exposure to LPS or IL-1 upregulates levels of IL-1RII, a nonfunctional receptor for IL-1α and IL-1β that binds IL-1 but fails to trigger intracellular signaling (Han and Ulevitch 2005;Pousset et al. >>2001<<). IL-1RII exists in membrane-bound and secreted forms, and recent data suggest that alpha- (BACE1), beta- (BACE2), and gamma-secretase activity contributes to production of the soluble form (Kuhn et al. 2007). Garlind et al. (1999) have
n3:mentions
n4:11723165
Subject Item
_:vb5759343
rdf:type
n3:Context
rdf:value
IL-1RII exists in membrane-bound and secreted forms, and recent data suggest that alpha- (BACE1), beta- (BACE2), and gamma-secretase activity contributes to production of the soluble form (Kuhn et al. >>2007<<). Garlind et al. (1999) have shown that soluble IL-1RII levels are increased in the CSF of AD patients compared to age-matched control individuals. IL receptor antagonist (IL-1Ra) is a soluble nonfunctional ligand of the IL-1 receptor
n3:mentions
n4:17307738
Subject Item
_:vb5759344
rdf:type
n3:Context
rdf:value
Garlind et al. (>>1999<<) have shown that soluble IL-1RII levels are increased in the CSF of AD patients compared to age-matched control individuals.
n3:mentions
n4:10216202
Subject Item
_:vb5759345
rdf:type
n3:Context
rdf:value
IL receptor antagonist (IL-1Ra) is a soluble nonfunctional ligand of the IL-1 receptor family that also reduces IL-1-mediated proinflammatory signaling (Pousset et al. >>2001<<). In addition, soluble receptors for other cytokines such as IL-6 and TNF-α are shed to the extracellular matrix where they compete with the functional membrane receptor for cytokine binding and effectively reduce cell signaling (Han and
n3:mentions
n4:11723165
Subject Item
_:vb5759346
rdf:type
n3:Context
rdf:value
soluble receptors for other cytokines such as IL-6 and TNF-α are shed to the extracellular matrix where they compete with the functional membrane receptor for cytokine binding and effectively reduce cell signaling (Han and Ulevitch >>2005<<; Kariko et al. 2004; Pousset et al. 2001; Serhan and Levy 2003).
n3:mentions
n4:16369559
Subject Item
_:vb5759347
rdf:type
n3:Context
rdf:value
for other cytokines such as IL-6 and TNF-α are shed to the extracellular matrix where they compete with the functional membrane receptor for cytokine binding and effectively reduce cell signaling (Han and Ulevitch 2005; Kariko et al. >>2004<<; Pousset et al. 2001; Serhan and Levy 2003).
n3:mentions
n4:15545925
Subject Item
_:vb5759348
rdf:type
n3:Context
rdf:value
such as IL-6 and TNF-α are shed to the extracellular matrix where they compete with the functional membrane receptor for cytokine binding and effectively reduce cell signaling (Han and Ulevitch 2005; Kariko et al. 2004; Pousset et al. >>2001<<; Serhan and Levy 2003).
n3:mentions
n4:11723165
Subject Item
_:vb5759349
rdf:type
n3:Context
rdf:value
are shed to the extracellular matrix where they compete with the functional membrane receptor for cytokine binding and effectively reduce cell signaling (Han and Ulevitch 2005; Kariko et al. 2004; Pousset et al. 2001; Serhan and Levy >>2003<<).
n3:mentions
n4:12947982
Subject Item
_:vb5759350
rdf:type
n2:Section
dc:title
repair and resolution: changing the macrophage activation state
n2:contains
_:vb5759357 _:vb5759358 _:vb5759359 _:vb5759352 _:vb5759353 _:vb5759354 _:vb5759355 _:vb5759351 _:vb5759388 _:vb5759389 _:vb5759390 _:vb5759384 _:vb5759385 _:vb5759386 _:vb5759387 _:vb5759380 _:vb5759381 _:vb5759382 _:vb5759383 _:vb5759376 _:vb5759377 _:vb5759378 _:vb5759379 _:vb5759372 _:vb5759373 _:vb5759374 _:vb5759375 _:vb5759368 _:vb5759369 _:vb5759370 _:vb5759371 _:vb5759364 _:vb5759365 _:vb5759366 _:vb5759367 _:vb5759360 _:vb5759361 _:vb5759362 _:vb5759363 _:vb5759356
Subject Item
_:vb5759351
rdf:type
n3:Context
rdf:value
Anti-inflammatory cytokines are the predominant induction signal (Hamilton et al. >>1999<<; Martinez et al. 2008; Sandler et al. 2003; Scotton et al. 2005).
n3:mentions
n4:10725793
Subject Item
_:vb5759352
rdf:type
n3:Context
rdf:value
Anti-inflammatory cytokines are the predominant induction signal (Hamilton et al. 1999; Martinez et al. >>2008<<; Sandler et al. 2003; Scotton et al. 2005).
n3:mentions
n4:17981560
Subject Item
_:vb5759353
rdf:type
n3:Context
rdf:value
Anti-inflammatory cytokines are the predominant induction signal (Hamilton et al. 1999; Martinez et al. 2008; Sandler et al. >>2003<<; Scotton et al. 2005).
n3:mentions
n4:14500663
Subject Item
_:vb5759354
rdf:type
n3:Context
rdf:value
Anti-inflammatory cytokines are the predominant induction signal (Hamilton et al. 1999; Martinez et al. 2008; Sandler et al. 2003; Scotton et al. >>2005<<). Derived primarily from studies in peripheral tissues, four major anti-inflammatory cytokines have been identified: IL-4, IL-13, IL-10, and TGF-β (Bogdan et al. 1991; Hamilton et al. 1999; Gordon and Taylor 2005; Martinez et al. 2008;
n3:mentions
n4:15634905
Subject Item
_:vb5759355
rdf:type
n3:Context
rdf:value
Derived primarily from studies in peripheral tissues, four major anti-inflammatory cytokines have been identified: IL-4, IL-13, IL-10, and TGF-β (Bogdan et al. >>1991<<; Hamilton et al. 1999; Gordon and Taylor 2005; Martinez et al. 2008; Mills et al. 2000).
n3:mentions
n4:1744584
Subject Item
_:vb5759356
rdf:type
n3:Context
rdf:value
Derived primarily from studies in peripheral tissues, four major anti-inflammatory cytokines have been identified: IL-4, IL-13, IL-10, and TGF-β (Bogdan et al. 1991; Hamilton et al. >>1999<<; Gordon and Taylor 2005; Martinez et al. 2008; Mills et al. 2000).
n3:mentions
n4:10725793
Subject Item
_:vb5759357
rdf:type
n3:Context
rdf:value
Derived primarily from studies in peripheral tissues, four major anti-inflammatory cytokines have been identified: IL-4, IL-13, IL-10, and TGF-β (Bogdan et al. 1991; Hamilton et al. 1999; Gordon and Taylor >>2005<<; Martinez et al. 2008; Mills et al. 2000).
n3:mentions
n4:16322748
Subject Item
_:vb5759358
rdf:type
n3:Context
rdf:value
Derived primarily from studies in peripheral tissues, four major anti-inflammatory cytokines have been identified: IL-4, IL-13, IL-10, and TGF-β (Bogdan et al. 1991; Hamilton et al. 1999; Gordon and Taylor 2005; Martinez et al. >>2008<<; Mills et al. 2000).
n3:mentions
n4:17981560
Subject Item
_:vb5759359
rdf:type
n3:Context
rdf:value
from studies in peripheral tissues, four major anti-inflammatory cytokines have been identified: IL-4, IL-13, IL-10, and TGF-β (Bogdan et al. 1991; Hamilton et al. 1999; Gordon and Taylor 2005; Martinez et al. 2008; Mills et al. >>2000<<). Stimulation of peripheral macrophages with IL-4, IL-13, IL-10, or TGF-β antagonizes classical activation pathways and induces new genes and proteins involved specifically in tissue repair and reconstruction.
n3:mentions
n4:10843666
Subject Item
_:vb5759360
rdf:type
n3:Context
rdf:value
Instead, IL-4, IL-13, TGF-β, and IL-10 are each produced within the brain and are released by either microglia, astrocytes, or, in some cases, neurons (Brodie et al. >>1998<<; Finch et al. 1993; Glezer et al. 2007; Grommes et al. 2008; Ledeboer et al. 2000; Morgan et al. 1993; Shin et al. 2004; Suzuki et al. 2005; Szczepanik et al. 2001).
n3:mentions
n4:9521602
Subject Item
_:vb5759361
rdf:type
n3:Context
rdf:value
Instead, IL-4, IL-13, TGF-β, and IL-10 are each produced within the brain and are released by either microglia, astrocytes, or, in some cases, neurons (Brodie et al. 1998; Finch et al. >>1993<<; Glezer et al. 2007; Grommes et al. 2008; Ledeboer et al. 2000; Morgan et al. 1993; Shin et al. 2004; Suzuki et al. 2005; Szczepanik et al. 2001).
n3:mentions
n4:8300749
Subject Item
_:vb5759362
rdf:type
n3:Context
rdf:value
Instead, IL-4, IL-13, TGF-β, and IL-10 are each produced within the brain and are released by either microglia, astrocytes, or, in some cases, neurons (Brodie et al. 1998; Finch et al. 1993; Glezer et al. >>2007<<; Grommes et al. 2008; Ledeboer et al. 2000; Morgan et al. 1993; Shin et al. 2004; Suzuki et al. 2005; Szczepanik et al. 2001).
n3:mentions
n4:17459594
Subject Item
_:vb5759363
rdf:type
n3:Context
rdf:value
Instead, IL-4, IL-13, TGF-β, and IL-10 are each produced within the brain and are released by either microglia, astrocytes, or, in some cases, neurons (Brodie et al. 1998; Finch et al. 1993; Glezer et al. 2007; Grommes et al. >>2008<<; Ledeboer et al. 2000; Morgan et al. 1993; Shin et al. 2004; Suzuki et al. 2005; Szczepanik et al. 2001).
n3:mentions
n4:18247125
Subject Item
_:vb5759364
rdf:type
n3:Context
rdf:value
IL-13, TGF-β, and IL-10 are each produced within the brain and are released by either microglia, astrocytes, or, in some cases, neurons (Brodie et al. 1998; Finch et al. 1993; Glezer et al. 2007; Grommes et al. 2008; Ledeboer et al. >>2000<<; Morgan et al. 1993; Shin et al. 2004; Suzuki et al. 2005; Szczepanik et al. 2001).
n3:mentions
n4:10719355
Subject Item
_:vb5759365
rdf:type
n3:Context
rdf:value
IL-10 are each produced within the brain and are released by either microglia, astrocytes, or, in some cases, neurons (Brodie et al. 1998; Finch et al. 1993; Glezer et al. 2007; Grommes et al. 2008; Ledeboer et al. 2000; Morgan et al. >>1993<<; Shin et al. 2004; Suzuki et al. 2005; Szczepanik et al. 2001). The signal for their production is thought to be the original pathogens and/or secondary factors secreted as a result of paracrine or autocrine activity.
n3:mentions
n4:8491285
Subject Item
_:vb5759366
rdf:type
n3:Context
rdf:value
within the brain and are released by either microglia, astrocytes, or, in some cases, neurons (Brodie et al. 1998; Finch et al. 1993; Glezer et al. 2007; Grommes et al. 2008; Ledeboer et al. 2000; Morgan et al. 1993; Shin et al. >>2004<<; Suzuki et al. 2005; Szczepanik et al. 2001). The signal for their production is thought to be the original pathogens and/or secondary factors secreted as a result of paracrine or autocrine activity.
n3:mentions
n4:15042582
Subject Item
_:vb5759367
rdf:type
n3:Context
rdf:value
and are released by either microglia, astrocytes, or, in some cases, neurons (Brodie et al. 1998; Finch et al. 1993; Glezer et al. 2007; Grommes et al. 2008; Ledeboer et al. 2000; Morgan et al. 1993; Shin et al. 2004; Suzuki et al. >>2005<<; Szczepanik et al. 2001). The signal for their production is thought to be the original pathogens and/or secondary factors secreted as a result of paracrine or autocrine activity.
n3:mentions
n4:15619519
Subject Item
_:vb5759368
rdf:type
n3:Context
rdf:value
microglia, astrocytes, or, in some cases, neurons (Brodie et al. 1998; Finch et al. 1993; Glezer et al. 2007; Grommes et al. 2008; Ledeboer et al. 2000; Morgan et al. 1993; Shin et al. 2004; Suzuki et al. 2005; Szczepanik et al. >>2001<<). The signal for their production is thought to be the original pathogens and/or secondary factors secreted as a result of paracrine or autocrine activity.
n3:mentions
n4:11137576
Subject Item
_:vb5759369
rdf:type
n3:Context
rdf:value
However, particularly for IL-4 and IL-13 (Ponomarev et al. >>2007<<), messenger RNA (mRNA) and protein levels are highly variable and they may be found only under specific types of induction.
n3:mentions
n4:17913905
Subject Item
_:vb5759370
rdf:type
n3:Context
rdf:value
microglia) may be exposed to higher levels of IL-4 or IL-10 from encounters with activated T cells or regulatory T cells that have traversed the blood–brain barrier to enter the brain parenchyma around the blood vessels (Perry et al. >>2007<<; Schwartz et al. 2009; Tiemessen et al. 2007; Villoslada et al. 2008).
n3:mentions
n4:17220915
Subject Item
_:vb5759371
rdf:type
n3:Context
rdf:value
to higher levels of IL-4 or IL-10 from encounters with activated T cells or regulatory T cells that have traversed the blood–brain barrier to enter the brain parenchyma around the blood vessels (Perry et al. 2007; Schwartz et al. >>2009<<; Tiemessen et al. 2007; Villoslada et al. 2008).
n3:mentions
n4:19103265
Subject Item
_:vb5759372
rdf:type
n3:Context
rdf:value
IL-4 or IL-10 from encounters with activated T cells or regulatory T cells that have traversed the blood–brain barrier to enter the brain parenchyma around the blood vessels (Perry et al. 2007; Schwartz et al. 2009; Tiemessen et al. >>2007<<; Villoslada et al. 2008).
n3:mentions
n4:18042719
Subject Item
_:vb5759373
rdf:type
n3:Context
rdf:value
with activated T cells or regulatory T cells that have traversed the blood–brain barrier to enter the brain parenchyma around the blood vessels (Perry et al. 2007; Schwartz et al. 2009; Tiemessen et al. 2007; Villoslada et al. >>2008<<).
n3:mentions
n4:18534912
Subject Item
_:vb5759374
rdf:type
n3:Context
rdf:value
The term was originally derived from the association of this macrophage state with the TH2 adaptive immune responses and, hence, the term M2 has also been used to describe alternatively activated macrophages (Edwards et al. >>2006<<; Mantovani et al. 2002; Mills et al. 2000; Mosser 2003).
n3:mentions
n4:16905575
Subject Item
_:vb5759375
rdf:type
n3:Context
rdf:value
originally derived from the association of this macrophage state with the TH2 adaptive immune responses and, hence, the term M2 has also been used to describe alternatively activated macrophages (Edwards et al. 2006; Mantovani et al. >>2002<<; Mills et al. 2000; Mosser 2003).
n3:mentions
n4:12401408
Subject Item
_:vb5759376
rdf:type
n3:Context
rdf:value
from the association of this macrophage state with the TH2 adaptive immune responses and, hence, the term M2 has also been used to describe alternatively activated macrophages (Edwards et al. 2006; Mantovani et al. 2002; Mills et al. >>2000<<; Mosser 2003).
n3:mentions
n4:10843666
Subject Item
_:vb5759377
rdf:type
n3:Context
rdf:value
of this macrophage state with the TH2 adaptive immune responses and, hence, the term M2 has also been used to describe alternatively activated macrophages (Edwards et al. 2006; Mantovani et al. 2002; Mills et al. 2000; Mosser >>2003<<). However, recent studies have suggested that applying a single nomenclature to macrophages exhibiting repair activation states does not adequately describe the differences between macrophages with this general functional phenotype.
n3:mentions
n4:12554797
Subject Item
_:vb5759378
rdf:type
n3:Context
rdf:value
To partially remedy this problem, Simon Gordon (>>2003<<; Gordon and Taylor 2005) has proposed to restrict the use of “alternative activation” to describe macrophages exposed primarily to IL-4 or IL-13.
n3:mentions
n4:12511873
Subject Item
_:vb5759379
rdf:type
n3:Context
rdf:value
To partially remedy this problem, Simon Gordon (2003; Gordon and Taylor >>2005<<) has proposed to restrict the use of “alternative activation” to describe macrophages exposed primarily to IL-4 or IL-13.
n3:mentions
n4:16322748
Subject Item
_:vb5759380
rdf:type
n3:Context
rdf:value
Accordingly, a third subtype of macrophage activation has been identified and has been termed “acquired deactivation” by Gordon (>>2003<<; Gordon and Taylor, 2005).
n3:mentions
n4:12511873
Subject Item
_:vb5759381
rdf:type
n3:Context
rdf:value
Accordingly, a third subtype of macrophage activation has been identified and has been termed “acquired deactivation” by Gordon (2003; Gordon and Taylor, >>2005<<). The acquired deactivation subtype incorporates a mixed-phenotype population that exhibits immunosuppression and is associated with uptake of apoptotic cells. Acquired deactivation is distinguished from alternative activation by the type
n3:mentions
n4:16322748
Subject Item
_:vb5759382
rdf:type
n3:Context
rdf:value
In addition, major histocompatibility complex (MHC) class II antigens and their costimulatory proteins are suppressed, making this macrophage subtype less effective at presenting antigen to invading T cells (Gordon >>2003<<; Williams et al. 1996).
n3:mentions
n4:12511873
Subject Item
_:vb5759383
rdf:type
n3:Context
rdf:value
addition, major histocompatibility complex (MHC) class II antigens and their costimulatory proteins are suppressed, making this macrophage subtype less effective at presenting antigen to invading T cells (Gordon 2003; Williams et al. >>1996<<). The signaling mechanisms for IL-10 require STAT3 and, for TGF-ß, Smad (Li et al. 2006; Ricchetti et al. 2004; Williams et al. 2007).
n3:mentions
n4:8808789
Subject Item
_:vb5759384
rdf:type
n3:Context
rdf:value
The signaling mechanisms for IL-10 require STAT3 and, for TGF-ß, Smad (Li et al. >>2006<<; Ricchetti et al. 2004; Williams et al. 2007).
n3:mentions
n4:16551245
Subject Item
_:vb5759385
rdf:type
n3:Context
rdf:value
The signaling mechanisms for IL-10 require STAT3 and, for TGF-ß, Smad (Li et al. 2006; Ricchetti et al. >>2004<<; Williams et al. 2007).
n3:mentions
n4:15240748
Subject Item
_:vb5759386
rdf:type
n3:Context
rdf:value
The signaling mechanisms for IL-10 require STAT3 and, for TGF-ß, Smad (Li et al. 2006; Ricchetti et al. 2004; Williams et al. >>2007<<). Acquired deactivation can also be induced by the phagocytosis of apoptotic cells, which is known to increase production of TGF-ß and IL-10 (Freire-de-Lima et al. 2006; Gregory and Devitt 2004; Griffiths et al. 2009; Li et al. 2006).
n3:mentions
n4:17194701
Subject Item
_:vb5759387
rdf:type
n3:Context
rdf:value
Acquired deactivation can also be induced by the phagocytosis of apoptotic cells, which is known to increase production of TGF-ß and IL-10 (Freire-de-Lima et al. >>2006<<; Gregory and Devitt 2004; Griffiths et al. 2009; Li et al. 2006).
n3:mentions
n4:17056601
Subject Item
_:vb5759388
rdf:type
n3:Context
rdf:value
Acquired deactivation can also be induced by the phagocytosis of apoptotic cells, which is known to increase production of TGF-ß and IL-10 (Freire-de-Lima et al. 2006; Gregory and Devitt >>2004<<; Griffiths et al. 2009; Li et al. 2006).
n3:mentions
n4:15312130
Subject Item
_:vb5759389
rdf:type
n3:Context
rdf:value
Acquired deactivation can also be induced by the phagocytosis of apoptotic cells, which is known to increase production of TGF-ß and IL-10 (Freire-de-Lima et al. 2006; Gregory and Devitt 2004; Griffiths et al. >>2009<<; Li et al. 2006).
n3:mentions
n4:19225414
Subject Item
_:vb5759390
rdf:type
n3:Context
rdf:value
Acquired deactivation can also be induced by the phagocytosis of apoptotic cells, which is known to increase production of TGF-ß and IL-10 (Freire-de-Lima et al. 2006; Gregory and Devitt 2004; Griffiths et al. 2009; Li et al. >>2006<<). Although the above definitions of alternative activation are not universally accepted, Table 2 provides known characteristics of each macrophage phenotype including induction agents, functions, and key genes mediating those effects.
n3:mentions
n4:16551245
Subject Item
_:vb5759391
rdf:type
n2:Section
dc:title
alternative activation
n2:contains
_:vb5759416 _:vb5759417 _:vb5759418 _:vb5759419 _:vb5759420 _:vb5759421 _:vb5759408 _:vb5759409 _:vb5759410 _:vb5759411 _:vb5759412 _:vb5759413 _:vb5759414 _:vb5759415 _:vb5759400 _:vb5759401 _:vb5759402 _:vb5759403 _:vb5759404 _:vb5759405 _:vb5759406 _:vb5759407 _:vb5759392 _:vb5759393 _:vb5759394 _:vb5759395 _:vb5759396 _:vb5759397 _:vb5759398 _:vb5759399
Subject Item
_:vb5759392
rdf:type
n3:Context
rdf:value
Interestingly, many parasitic organisms have subverted alternative activation as a means to enhance their survival within cells or tissues (Noel et al. >>2004<<; Raes et al. 2007; Vincendeau et al. 2003; Wynn et al. 2004).
n3:mentions
n4:15036034
Subject Item
_:vb5759393
rdf:type
n3:Context
rdf:value
Interestingly, many parasitic organisms have subverted alternative activation as a means to enhance their survival within cells or tissues (Noel et al. 2004; Raes et al. >>2007<<; Vincendeau et al. 2003; Wynn et al. 2004).
n3:mentions
n4:17628461
Subject Item
_:vb5759394
rdf:type
n3:Context
rdf:value
Interestingly, many parasitic organisms have subverted alternative activation as a means to enhance their survival within cells or tissues (Noel et al. 2004; Raes et al. 2007; Vincendeau et al. >>2003<<; Wynn et al. 2004).
n3:mentions
n4:12488215
Subject Item
_:vb5759395
rdf:type
n3:Context
rdf:value
Interestingly, many parasitic organisms have subverted alternative activation as a means to enhance their survival within cells or tissues (Noel et al. 2004; Raes et al. 2007; Vincendeau et al. 2003; Wynn et al. >>2004<<). Compared to classically activated macrophages, alternatively activated macrophages do not express high levels of proinflammatory cytokines. Instead, NOS2, IL-12, IL-1β, IL-6, and TNF-α mRNA and protein levels in LPS-stimulated microglia
n3:mentions
n4:15361239
Subject Item
_:vb5759396
rdf:type
n3:Context
rdf:value
Instead, NOS2, IL-12, IL-1β, IL-6, and TNF-α mRNA and protein levels in LPS-stimulated microglia and mixed glial cultures are suppressed by IL-4 and IL-13 (Colton et al. 2006a; Kitamura et al. 2000; Ledeboer et al. 2000; Lee et al. 2002; Lyons et al. 2007b; Ponomarev et al. 2007).
n3:mentions
n4:17005052
Subject Item
_:vb5759397
rdf:type
n3:Context
rdf:value
Instead, NOS2, IL-12, IL-1β, IL-6, and TNF-α mRNA and protein levels in LPS-stimulated microglia and mixed glial cultures are suppressed by IL-4 and IL-13 (Colton et al. 2006a; Kitamura et al. >>2000<<; Ledeboer et al. 2000; Lee et al. 2002; Lyons et al. 2007b; Ponomarev et al. 2007).
n3:mentions
n4:10814787
Subject Item
_:vb5759398
rdf:type
n3:Context
rdf:value
Instead, NOS2, IL-12, IL-1β, IL-6, and TNF-α mRNA and protein levels in LPS-stimulated microglia and mixed glial cultures are suppressed by IL-4 and IL-13 (Colton et al. 2006a; Kitamura et al. 2000; Ledeboer et al. >>2000<<; Lee et al. 2002; Lyons et al. 2007b; Ponomarev et al. 2007).
n3:mentions
n4:10719355
Subject Item
_:vb5759399
rdf:type
n3:Context
rdf:value
Instead, NOS2, IL-12, IL-1β, IL-6, and TNF-α mRNA and protein levels in LPS-stimulated microglia and mixed glial cultures are suppressed by IL-4 and IL-13 (Colton et al. 2006a; Kitamura et al. 2000; Ledeboer et al. 2000; Lee et al. >>2002<<; Lyons et al. 2007b; Ponomarev et al. 2007). In general, either IL-13 or IL-4 stimulation of macrophages results in a similar gene profile.
n3:mentions
n4:12111820
Subject Item
_:vb5759400
rdf:type
n3:Context
rdf:value
IL-1β, IL-6, and TNF-α mRNA and protein levels in LPS-stimulated microglia and mixed glial cultures are suppressed by IL-4 and IL-13 (Colton et al. 2006a; Kitamura et al. 2000; Ledeboer et al. 2000; Lee et al. 2002; Lyons et al. 2007b; Ponomarev et al. 2007). In general, either IL-13 or IL-4 stimulation of macrophages results in a similar gene profile.
n3:mentions
n4:17670977
Subject Item
_:vb5759401
rdf:type
n3:Context
rdf:value
mRNA and protein levels in LPS-stimulated microglia and mixed glial cultures are suppressed by IL-4 and IL-13 (Colton et al. 2006a; Kitamura et al. 2000; Ledeboer et al. 2000; Lee et al. 2002; Lyons et al. 2007b; Ponomarev et al. >>2007<<). In general, either IL-13 or IL-4 stimulation of macrophages results in a similar gene profile.
n3:mentions
n4:17913905
Subject Item
_:vb5759402
rdf:type
n3:Context
rdf:value
Scotton et al. (>>2005<<) have provided a detailed analysis of gene expression in IL-13-treated human monocytes.
n3:mentions
n4:15634905
Subject Item
_:vb5759403
rdf:type
n3:Context
rdf:value
STAT6 is then recruited to the receptor where it is phosphorylated and subsequently translocates to the nucleus (Scotton et al. >>2005<<). Like other STAT proteins, STAT6 binds DNA and can rapidly transduce membrane signals to gene induction during inflammation. The importance of STAT6 to the gene switch is shown in studies on knockout mice where the genetic removal of
n3:mentions
n4:15634905
Subject Item
_:vb5759404
rdf:type
n3:Context
rdf:value
The importance of STAT6 to the gene switch is shown in studies on knockout mice where the genetic removal of STAT6 results in lost responsiveness to IL-4 or IL-13 and failure to induce the alternative activation state (Pfitzner et al. >>2004<<; Zhu et al. 2001).
n3:mentions
n4:15379672
Subject Item
_:vb5759405
rdf:type
n3:Context
rdf:value
STAT6 to the gene switch is shown in studies on knockout mice where the genetic removal of STAT6 results in lost responsiveness to IL-4 or IL-13 and failure to induce the alternative activation state (Pfitzner et al. 2004; Zhu et al. >>2001<<).
n3:mentions
n4:11390477
Subject Item
_:vb5759406
rdf:type
n3:Context
rdf:value
IL-4 receptors are found on microglia and astrocytes and are expressed at high density on multiple types of glial tumors (Kawakami et al. >>2001<<). IL-13 receptors are found in rat and human brain, suggesting that IL-13 signaling is also observed in the brain (Lee et al. 2002; Wu et al. 2008). Our laboratory has shown that microglia demonstrate an anti-inflammatory alternative
n3:mentions
n4:11939409
Subject Item
_:vb5759407
rdf:type
n3:Context
rdf:value
IL-13 receptors are found in rat and human brain, suggesting that IL-13 signaling is also observed in the brain (Lee et al. >>2002<<; Wu et al. 2008).
n3:mentions
n4:12111820
Subject Item
_:vb5759408
rdf:type
n3:Context
rdf:value
IL-13 receptors are found in rat and human brain, suggesting that IL-13 signaling is also observed in the brain (Lee et al. 2002; Wu et al. >>2008<<). Our laboratory has shown that microglia demonstrate an anti-inflammatory alternative activation phenotype when stimulated with IL-4 or IL-13. Treatment of IFN-γ-activated BV2 microglia or primary mouse microglia in culture with IL-4 or
n3:mentions
n4:18848892
Subject Item
_:vb5759409
rdf:type
n3:Context
rdf:value
IL-4 or IL-13 treatment of microglia resulted in increased mRNA expression of arginase 1 (AG1), mannose receptor (MRC1), found in inflammatory zone 1 (FIZZ1), and Ym1 (Colton et al. 2006a; Lyons et al. 2007a).
n3:mentions
n4:17005052
Subject Item
_:vb5759410
rdf:type
n3:Context
rdf:value
IL-4 or IL-13 treatment of microglia resulted in increased mRNA expression of arginase 1 (AG1), mannose receptor (MRC1), found in inflammatory zone 1 (FIZZ1), and Ym1 (Colton et al. 2006a; Lyons et al. 2007a). In addition, treatment with Aβ peptides plus IL-4 increased microglial expression of AG1 by approximately 70% compared to IL-4 alone, suggesting that Aβ may directly regulate some components of alternative activation. Using Aβ peptides
n3:mentions
n4:17250684
Subject Item
_:vb5759411
rdf:type
n3:Context
rdf:value
Using Aβ peptides as the immune stimulus, Lyons et al. (2007a) and Lee et al. (2002) have shown that IL-4 reduces Aβ-mediated proinflammatory gene expression in microglia in vitro and in vivo.
n3:mentions
n4:17250684
Subject Item
_:vb5759412
rdf:type
n3:Context
rdf:value
Using Aβ peptides as the immune stimulus, Lyons et al. (2007a) and Lee et al. (>>2002<<) have shown that IL-4 reduces Aβ-mediated proinflammatory gene expression in microglia in vitro and in vivo.
n3:mentions
n4:12111820
Subject Item
_:vb5759413
rdf:type
n3:Context
rdf:value
mRNA expression is found for IL-10, TGF-β, CD23 (the low-affinity IgE receptor, FcεRII), insulin growth factor 1 (IGF-1), nerve growth factor (NGF), and peroxisome proliferation activation receptor gamma (PPAR-γ; Brodie et al. >>1998<<; Kitamura et al. 2000; Odegaard et al. 2007; van Rossum et al. 2008).
n3:mentions
n4:9521602
Subject Item
_:vb5759414
rdf:type
n3:Context
rdf:value
is found for IL-10, TGF-β, CD23 (the low-affinity IgE receptor, FcεRII), insulin growth factor 1 (IGF-1), nerve growth factor (NGF), and peroxisome proliferation activation receptor gamma (PPAR-γ; Brodie et al. 1998; Kitamura et al. >>2000<<; Odegaard et al. 2007; van Rossum et al. 2008). These genes are generally associated with the continued physiological requirements for repair and reconstruction after injury, including adaptive immunity and metabolism.
n3:mentions
n4:10814787
Subject Item
_:vb5759415
rdf:type
n3:Context
rdf:value
TGF-β, CD23 (the low-affinity IgE receptor, FcεRII), insulin growth factor 1 (IGF-1), nerve growth factor (NGF), and peroxisome proliferation activation receptor gamma (PPAR-γ; Brodie et al. 1998; Kitamura et al. 2000; Odegaard et al. >>2007<<; van Rossum et al. 2008). These genes are generally associated with the continued physiological requirements for repair and reconstruction after injury, including adaptive immunity and metabolism.
n3:mentions
n4:17515919
Subject Item
_:vb5759416
rdf:type
n3:Context
rdf:value
IgE receptor, FcεRII), insulin growth factor 1 (IGF-1), nerve growth factor (NGF), and peroxisome proliferation activation receptor gamma (PPAR-γ; Brodie et al. 1998; Kitamura et al. 2000; Odegaard et al. 2007; van Rossum et al. >>2008<<). These genes are generally associated with the continued physiological requirements for repair and reconstruction after injury, including adaptive immunity and metabolism.
n3:mentions
n4:18069669
Subject Item
_:vb5759417
rdf:type
n3:Context
rdf:value
PPAR-α, δ, and γ, ligand-activated transcription factors whose distinct expression patterns and ligand specificities mediate different biological functions through targeting of genes associated with energy metabolism (Odegaard et al. >>2007<<). PPAR-γ upregulates expression of genes involved in high-density lipoprotein metabolism, downregulates cholesterol esterification, and inhibits the production of inflammatory mediators.
n3:mentions
n4:17515919
Subject Item
_:vb5759418
rdf:type
n3:Context
rdf:value
Although tissue-specific differences have been observed, Odegaard et al. (>>2007<<) have recently shown that IL-4-mediated upregulation of alternative activation genes depends highly on PPAR-γ.
n3:mentions
n4:17515919
Subject Item
_:vb5759419
rdf:type
n3:Context
rdf:value
Gene screens of IL-13-treated cells have shown a threefold to fourfold increase in PPAR-γ mRNA expression (Scotton et al. >>2005<<). Upregulation of IGF-1 and its insulin-like regulation of glucose during alternative activation further couples metabolism to repair (Rajpathak et al. 2009). Finally, IL-4 or IL-13 treatment increases CD23 expression in human macrophages.
n3:mentions
n4:15634905
Subject Item
_:vb5759420
rdf:type
n3:Context
rdf:value
Upregulation of IGF-1 and its insulin-like regulation of glucose during alternative activation further couples metabolism to repair (Rajpathak et al. >>2009<<). Finally, IL-4 or IL-13 treatment increases CD23 expression in human macrophages. While CD23 deficiency leaves mice with higher circulating levels of IgE, IL-4-induced CD23 overexpression is generally believed to depress IgE levels and
n3:mentions
n4:19145587
Subject Item
_:vb5759421
rdf:type
n3:Context
rdf:value
While CD23 deficiency leaves mice with higher circulating levels of IgE, IL-4-induced CD23 overexpression is generally believed to depress IgE levels and downregulate allergic-type reactions during chronic disease (Ford et al. >>2006<<).
n3:mentions
n4:17324389
Subject Item
_:vb5759422
rdf:type
n2:Section
dc:title
lectins and alternative activation—mannose receptor
n2:contains
_:vb5759423 _:vb5759448 _:vb5759449 _:vb5759450 _:vb5759451 _:vb5759444 _:vb5759445 _:vb5759446 _:vb5759447 _:vb5759440 _:vb5759441 _:vb5759442 _:vb5759443 _:vb5759436 _:vb5759437 _:vb5759438 _:vb5759439 _:vb5759432 _:vb5759433 _:vb5759434 _:vb5759435 _:vb5759428 _:vb5759429 _:vb5759430 _:vb5759431 _:vb5759424 _:vb5759425 _:vb5759426 _:vb5759427
Subject Item
_:vb5759423
rdf:type
n3:Context
rdf:value
These carbohydrate moieties are recognized by specific lectin binding sites on the macrophage membrane and, when bound, initiate signaling pathways within the macrophage (Taylor et al. 2005b). Multiple subtypes of lectin binding sites have been described (Taylor et al. 2005a) and include the mannose receptor (MR, MRC-1, CD206). MR is a member of the C-type lectin family and is not expressed on classically activated
n3:mentions
n4:15771589
Subject Item
_:vb5759424
rdf:type
n3:Context
rdf:value
Multiple subtypes of lectin binding sites have been described (Taylor et al. 2005a) and include the mannose receptor (MR, MRC-1, CD206).
n3:mentions
n4:15668126
Subject Item
_:vb5759425
rdf:type
n3:Context
rdf:value
cross-linking, followed by phagocytosis of the ligand and activation of a typical anti-inflammatory signaling pathway that results in decreased IL-12 and TNF-α and increased IL-10 and IL-1Ra mRNA and protein expression (Chieppa et al. >>2003<<; Kerrigan and Brown 2009; Pachter et al. 2003; Taylor et al. 2005a). MR activation is also critical for upregulation of MHC II expression and antigen presentation and helps to link innate and adaptive immunity.
n3:mentions
n4:14568928
Subject Item
_:vb5759426
rdf:type
n3:Context
rdf:value
phagocytosis of the ligand and activation of a typical anti-inflammatory signaling pathway that results in decreased IL-12 and TNF-α and increased IL-10 and IL-1Ra mRNA and protein expression (Chieppa et al. 2003; Kerrigan and Brown >>2009<<; Pachter et al. 2003; Taylor et al. 2005a). MR activation is also critical for upregulation of MHC II expression and antigen presentation and helps to link innate and adaptive immunity.
n3:mentions
n4:19261355
Subject Item
_:vb5759427
rdf:type
n3:Context
rdf:value
ligand and activation of a typical anti-inflammatory signaling pathway that results in decreased IL-12 and TNF-α and increased IL-10 and IL-1Ra mRNA and protein expression (Chieppa et al. 2003; Kerrigan and Brown 2009; Pachter et al. >>2003<<; Taylor et al. 2005a). MR activation is also critical for upregulation of MHC II expression and antigen presentation and helps to link innate and adaptive immunity.
n3:mentions
n4:12834104
Subject Item
_:vb5759428
rdf:type
n3:Context
rdf:value
of a typical anti-inflammatory signaling pathway that results in decreased IL-12 and TNF-α and increased IL-10 and IL-1Ra mRNA and protein expression (Chieppa et al. 2003; Kerrigan and Brown 2009; Pachter et al. 2003; Taylor et al. 2005a). MR activation is also critical for upregulation of MHC II expression and antigen presentation and helps to link innate and adaptive immunity.
n3:mentions
n4:15668126
Subject Item
_:vb5759429
rdf:type
n3:Context
rdf:value
Interestingly, Linehan et al. (>>1999<<, 2003) and Galea et al. (2005) have shown that MR expression in the brain is found primarily on perivascular microglia, a subtype of brain macrophages long known to have unique characteristics (Perry and Gordon 1988).
n3:mentions
n4:10377192
Subject Item
_:vb5759430
rdf:type
n3:Context
rdf:value
Interestingly, Linehan et al. (1999, >>2003<<) and Galea et al. (2005) have shown that MR expression in the brain is found primarily on perivascular microglia, a subtype of brain macrophages long known to have unique characteristics (Perry and Gordon 1988).
n3:mentions
n4:12920251
Subject Item
_:vb5759431
rdf:type
n3:Context
rdf:value
Interestingly, Linehan et al. (1999, 2003) and Galea et al. (>>2005<<) have shown that MR expression in the brain is found primarily on perivascular microglia, a subtype of brain macrophages long known to have unique characteristics (Perry and Gordon 1988).
n3:mentions
n4:15538754
Subject Item
_:vb5759432
rdf:type
n3:Context
rdf:value
Linehan et al. (1999, 2003) and Galea et al. (2005) have shown that MR expression in the brain is found primarily on perivascular microglia, a subtype of brain macrophages long known to have unique characteristics (Perry and Gordon >>1988<<). Their location at the brain–vasculature interface implies that enhancement of antigen presentation by MR activation at this site may be important in brain disease.
n3:mentions
n4:2465626
Subject Item
_:vb5759433
rdf:type
n3:Context
rdf:value
This location is likely to be more accessible to T-regulatory cells or other cells associated with the adaptive immune response (Soulet and Rivest >>2008<<). That perivascular microglia also express high levels of CD163 (Fabriek et al. 2005), the membrane scavenger receptor associated with uptake of hemoglobin/haptoglobin complexes, also supports a role for this type of microglia in brain
n3:mentions
n4:18487084
Subject Item
_:vb5759434
rdf:type
n3:Context
rdf:value
That perivascular microglia also express high levels of CD163 (Fabriek et al. >>2005<<), the membrane scavenger receptor associated with uptake of hemoglobin/haptoglobin complexes, also supports a role for this type of microglia in brain disease, as it suggests that these cells may be exposed to hemoglobin leaked from blood
n3:mentions
n4:16164022
Subject Item
_:vb5759435
rdf:type
n3:Context
rdf:value
CD163 expression is increased by IL-10 (Fabriek et al. >>2005<<; Schaer et al. 2002).
n3:mentions
n4:16164022
Subject Item
_:vb5759436
rdf:type
n3:Context
rdf:value
CD163 expression is increased by IL-10 (Fabriek et al. 2005; Schaer et al. >>2002<<). Both MR and CD163 are cleaved by metalloproteases and shed from the surface membrane, which could make it difficult to see changes in expression levels using immunocytochemistry, particularly in disease states where levels of matrix
n3:mentions
n4:12358930
Subject Item
_:vb5759437
rdf:type
n3:Context
rdf:value
Other lectins such as dectin 1 and 2 and DC-SIGN also play important roles in macrophage activation (Kerrigan and Brown >>2009<<; Taylor et al. 2005c). The polysaccharide ligands for these receptors are highly varied but can be found in most tissues.
n3:mentions
n4:19261355
Subject Item
_:vb5759438
rdf:type
n3:Context
rdf:value
Other lectins such as dectin 1 and 2 and DC-SIGN also play important roles in macrophage activation (Kerrigan and Brown 2009; Taylor et al. 2005c). The polysaccharide ligands for these receptors are highly varied but can be found in most tissues.
n3:mentions
n4:15940672
Subject Item
_:vb5759439
rdf:type
n3:Context
rdf:value
For example, Lewis X trisaccharides, a component of the lacto-N-fucopentose III glycan from parasites such as Schistosoma, are extremely potent inducers of alternative activation in macrophages (Atochina et al. >>2008<<). Similar glycan moieties are found in brain fucolipids, which are glycosphingolipids containing fucose (Taketomi et al. 1984). Chitin, an N-acetyl-B glucosamine-based component of molting worms and insect exoskeletons, initiates
n3:mentions
n4:18373667
Subject Item
_:vb5759440
rdf:type
n3:Context
rdf:value
Similar glycan moieties are found in brain fucolipids, which are glycosphingolipids containing fucose (Taketomi et al. >>1984<<). Chitin, an N-acetyl-B glucosamine-based component of molting worms and insect exoskeletons, initiates alternative activation of lung macrophages (Reese et al. 2007) and accumulates around brain amyloid deposits (Castellani et al. 2005;
n3:mentions
n4:6430048
Subject Item
_:vb5759441
rdf:type
n3:Context
rdf:value
Chitin, an N-acetyl-B glucosamine-based component of molting worms and insect exoskeletons, initiates alternative activation of lung macrophages (Reese et al. >>2007<<) and accumulates around brain amyloid deposits (Castellani et al. 2005; Sotgiu et al. 2008).
n3:mentions
n4:17450126
Subject Item
_:vb5759442
rdf:type
n3:Context
rdf:value
Chitin, an N-acetyl-B glucosamine-based component of molting worms and insect exoskeletons, initiates alternative activation of lung macrophages (Reese et al. 2007) and accumulates around brain amyloid deposits (Castellani et al. >>2005<<; Sotgiu et al. 2008). Proteins associated with chitin degradation (chitinase 3 like 1; see below) are also upregulated in AD, but their role in the brain remains largely unknown.
n3:mentions
n4:16248847
Subject Item
_:vb5759443
rdf:type
n3:Context
rdf:value
glucosamine-based component of molting worms and insect exoskeletons, initiates alternative activation of lung macrophages (Reese et al. 2007) and accumulates around brain amyloid deposits (Castellani et al. 2005; Sotgiu et al. >>2008<<). Proteins associated with chitin degradation (chitinase 3 like 1; see below) are also upregulated in AD, but their role in the brain remains largely unknown.
n3:mentions
n4:18485490
Subject Item
_:vb5759444
rdf:type
n3:Context
rdf:value
Dectin 1 was originally described as a dendritic cell receptor but more recently has been found on membranes of tissue macrophages, including microglia (Shah et al. >>2008<<; Taylor et al. 2005c; Willment et al. 2003).
n3:mentions
n4:18292498
Subject Item
_:vb5759445
rdf:type
n3:Context
rdf:value
Dectin 1 was originally described as a dendritic cell receptor but more recently has been found on membranes of tissue macrophages, including microglia (Shah et al. 2008; Taylor et al. 2005c; Willment et al. 2003).
n3:mentions
n4:15940672
Subject Item
_:vb5759446
rdf:type
n3:Context
rdf:value
Dectin 1 was originally described as a dendritic cell receptor but more recently has been found on membranes of tissue macrophages, including microglia (Shah et al. 2008; Taylor et al. 2005c; Willment et al. >>2003<<). In contrast, dectin 2 is primarily found on dendritic cells and some peripheral macrophages but not on brain microglia (Taylor et al. 2005c). Similar to MR, dectins are a subtype of C-type lectins and bind to beta 1,3 glucan, chitin,
n3:mentions
n4:14568930
Subject Item
_:vb5759447
rdf:type
n3:Context
rdf:value
In contrast, dectin 2 is primarily found on dendritic cells and some peripheral macrophages but not on brain microglia (Taylor et al. 2005c). Similar to MR, dectins are a subtype of C-type lectins and bind to beta 1,3 glucan, chitin, mannan residues, and zymosan—pathogen moieties that are commonly associated with fungi, including yeast. Dectin 1 mRNA and protein expressions
n3:mentions
n4:15940672
Subject Item
_:vb5759448
rdf:type
n3:Context
rdf:value
Dectin 1 mRNA and protein expressions on peripheral macrophages are increased by treatment with IL-4 or IL-13 (Willment et al. >>2003<<). However, instead of a downregulatory response typical of IL-4 stimulation, dectin 1 activation by IL-4 leads to TNF-α production and a subsequent proinflammatory secretory response that includes NADPH oxidase-mediated production of
n3:mentions
n4:14568930
Subject Item
_:vb5759449
rdf:type
n3:Context
rdf:value
response typical of IL-4 stimulation, dectin 1 activation by IL-4 leads to TNF-α production and a subsequent proinflammatory secretory response that includes NADPH oxidase-mediated production of superoxide anions (Shah et al. >>2008<<; Underhill 2007).
n3:mentions
n4:18292498
Subject Item
_:vb5759450
rdf:type
n3:Context
rdf:value
typical of IL-4 stimulation, dectin 1 activation by IL-4 leads to TNF-α production and a subsequent proinflammatory secretory response that includes NADPH oxidase-mediated production of superoxide anions (Shah et al. 2008; Underhill >>2007<<). On the other hand, beta-glucan-mediated activation of dectin 1 on microglia produced an abbreviated response without proinflammatory cytokine and chemokine secretion (Shah et al. 2008), although production of superoxide anion was still
n3:mentions
n4:17850483
Subject Item
_:vb5759451
rdf:type
n3:Context
rdf:value
On the other hand, beta-glucan-mediated activation of dectin 1 on microglia produced an abbreviated response without proinflammatory cytokine and chemokine secretion (Shah et al. >>2008<<), although production of superoxide anion was still observed.
n3:mentions
n4:18292498
Subject Item
_:vb5759452
rdf:type
n2:Section
dc:title
arginase–nos2 balance in alternative activation
n2:contains
_:vb5759453 _:vb5759454 _:vb5759455 _:vb5759476 _:vb5759477 _:vb5759478 _:vb5759479 _:vb5759472 _:vb5759473 _:vb5759474 _:vb5759475 _:vb5759484 _:vb5759485 _:vb5759486 _:vb5759480 _:vb5759481 _:vb5759482 _:vb5759483 _:vb5759460 _:vb5759461 _:vb5759462 _:vb5759463 _:vb5759456 _:vb5759457 _:vb5759458 _:vb5759459 _:vb5759468 _:vb5759469 _:vb5759470 _:vb5759471 _:vb5759464 _:vb5759465 _:vb5759466 _:vb5759467
Subject Item
_:vb5759453
rdf:type
n3:Context
rdf:value
1; Morris 2004a, b, 2007). In the brain, the primary enzymes that require arginine as the sole substrate are arginase and NOS, although arginine is also used to produce agmatine via arginine decarboxylase and for protein synthesis.
n3:mentions
n4:15465778 n4:15090903
Subject Item
_:vb5759454
rdf:type
n3:Context
rdf:value
1; Morris 2004a, b, >>2007<<). In the brain, the primary enzymes that require arginine as the sole substrate are arginase and NOS, although arginine is also used to produce agmatine via arginine decarboxylase and for protein synthesis.
n3:mentions
n4:17513435
Subject Item
_:vb5759455
rdf:type
n3:Context
rdf:value
The enzymatic action of NOS to produce citrulline and NO from the oxidation of arginine is now well-known (Marletta >>1994<<; Moncada and Higgs 1991), and all three enzymes that produce NO are found in the brain (Wiesinger 2001).
n3:mentions
n4:7522970
Subject Item
_:vb5759456
rdf:type
n3:Context
rdf:value
The enzymatic action of NOS to produce citrulline and NO from the oxidation of arginine is now well-known (Marletta 1994; Moncada and Higgs >>1991<<), and all three enzymes that produce NO are found in the brain (Wiesinger 2001).
n3:mentions
n4:1718757
Subject Item
_:vb5759457
rdf:type
n3:Context
rdf:value
The enzymatic action of NOS to produce citrulline and NO from the oxidation of arginine is now well-known (Marletta 1994; Moncada and Higgs 1991), and all three enzymes that produce NO are found in the brain (Wiesinger >>2001<<). Arginase expression and activity in the brain are less well known. Two isoforms of arginase are found: arginase I, an inducible cytoplasmic form; and arginase II, a constitutively expressed isoform believed to be localized to
n3:mentions
n4:11275358
Subject Item
_:vb5759458
rdf:type
n3:Context
rdf:value
Two isoforms of arginase are found: arginase I, an inducible cytoplasmic form; and arginase II, a constitutively expressed isoform believed to be localized to mitochondria (Braissant et al. >>1999<<; Cederbaum et al. 2004; Salimuddin et al. 1999; Yu et al. 2001, 2003).
n3:mentions
n4:10407171
Subject Item
_:vb5759459
rdf:type
n3:Context
rdf:value
Two isoforms of arginase are found: arginase I, an inducible cytoplasmic form; and arginase II, a constitutively expressed isoform believed to be localized to mitochondria (Braissant et al. 1999; Cederbaum et al. >>2004<<; Salimuddin et al. 1999; Yu et al. 2001, 2003).
n3:mentions
n4:15050972
Subject Item
_:vb5759460
rdf:type
n3:Context
rdf:value
isoforms of arginase are found: arginase I, an inducible cytoplasmic form; and arginase II, a constitutively expressed isoform believed to be localized to mitochondria (Braissant et al. 1999; Cederbaum et al. 2004; Salimuddin et al. >>1999<<; Yu et al. 2001, 2003).
n3:mentions
n4:10409134
Subject Item
_:vb5759461
rdf:type
n3:Context
rdf:value
are found: arginase I, an inducible cytoplasmic form; and arginase II, a constitutively expressed isoform believed to be localized to mitochondria (Braissant et al. 1999; Cederbaum et al. 2004; Salimuddin et al. 1999; Yu et al. >>2001<<, 2003). Arginase I is robustly expressed in the cerebellum, pons, medulla, and spinal cord with lower expression in the hippocampus and the entorhinal and temporal cortices, whereas arginase II appears to be expressed throughout the brain
n3:mentions
n4:11746358
Subject Item
_:vb5759462
rdf:type
n3:Context
rdf:value
are found: arginase I, an inducible cytoplasmic form; and arginase II, a constitutively expressed isoform believed to be localized to mitochondria (Braissant et al. 1999; Cederbaum et al. 2004; Salimuddin et al. 1999; Yu et al. 2001, >>2003<<). Arginase I is robustly expressed in the cerebellum, pons, medulla, and spinal cord with lower expression in the hippocampus and the entorhinal and temporal cortices, whereas arginase II appears to be expressed throughout the brain at a
n3:mentions
n4:12923240
Subject Item
_:vb5759463
rdf:type
n3:Context
rdf:value
expressed in the cerebellum, pons, medulla, and spinal cord with lower expression in the hippocampus and the entorhinal and temporal cortices, whereas arginase II appears to be expressed throughout the brain at a low level (Yu et al. >>2003<<). The enzymatic product of both the cytosolic and mitochondrial forms of arginase is ornithine.
n3:mentions
n4:12923240
Subject Item
_:vb5759464
rdf:type
n3:Context
rdf:value
However, as discussed in more detail below, collagen is not a dominant feature of the ECM in the brain, as it is only found around the cerebrovasculature (Busch and Silver >>2007<<). Fig.
n3:mentions
n4:17223033
Subject Item
_:vb5759465
rdf:type
n3:Context
rdf:value
Polyamines (putrescine, spermidine, and spermine) are multivalent cations essential for cell proliferation and differentiation (Thomas and Thomas >>2001<<; Wallace et al. 1981; Wallace et al. 2003).
n3:mentions
n4:11289306
Subject Item
_:vb5759466
rdf:type
n3:Context
rdf:value
Polyamines (putrescine, spermidine, and spermine) are multivalent cations essential for cell proliferation and differentiation (Thomas and Thomas 2001; Wallace et al. >>1981<<; Wallace et al. 2003).
n3:mentions
n4:7213741
Subject Item
_:vb5759467
rdf:type
n3:Context
rdf:value
Polyamines (putrescine, spermidine, and spermine) are multivalent cations essential for cell proliferation and differentiation (Thomas and Thomas 2001; Wallace et al. 1981; Wallace et al. >>2003<<). For example, polyamines interact with DNA to promote stabilization and condensation and, consequently, cell proliferation (Thomas and Thomas 2001). While generalized cell proliferation is not a major factor in brain repair due to the
n3:mentions
n4:13678416
Subject Item
_:vb5759468
rdf:type
n3:Context
rdf:value
For example, polyamines interact with DNA to promote stabilization and condensation and, consequently, cell proliferation (Thomas and Thomas >>2001<<). While generalized cell proliferation is not a major factor in brain repair due to the postmitotic state of mature neurons, altered neurogenesis in specific proliferative areas of the brain contribute to the replacement of neurons.
n3:mentions
n4:11289306
Subject Item
_:vb5759469
rdf:type
n3:Context
rdf:value
Polyamines have recently been shown to stimulate neuronal progenitor proliferation in the subgranular zone of the dentate gyrus and subventricular zone (Malaterre et al. >>2004<<). Finally, spermine can help protect neurons injured by exposure to proinflammatory cytokines by blocking NMDA channels and/or altering GluR1 and potassium (K) channel function (Williams 1997).
n3:mentions
n4:15233741
Subject Item
_:vb5759470
rdf:type
n3:Context
rdf:value
Finally, spermine can help protect neurons injured by exposure to proinflammatory cytokines by blocking NMDA channels and/or altering GluR1 and potassium (K) channel function (Williams >>1997<<).
n3:mentions
n4:9230104
Subject Item
_:vb5759471
rdf:type
n3:Context
rdf:value
The inverse association of arginase and NOS is based on the requirement of these two enzyme systems for arginine, the sole substrate of each enzyme (Morris et al. >>1998<<; Morris 2004b).
n3:mentions
n4:9814991
Subject Item
_:vb5759472
rdf:type
n3:Context
rdf:value
The inverse association of arginase and NOS is based on the requirement of these two enzyme systems for arginine, the sole substrate of each enzyme (Morris et al. 1998; Morris 2004b). Essentially, NOS and arginase compete for available intracellular arginine. While this does not seem likely based on Km values for the two enzymes (Km NOS = 3–10 μM; Km arginase = 3–10 mM), the time course of induction and the
n3:mentions
n4:15465778
Subject Item
_:vb5759473
rdf:type
n3:Context
rdf:value
Since NO-mediated nitrosylation, nitrosation, and nitration of bacterial proteins is an efficient way to kill bacteria (Ogawa et al. >>2001<<; Ren et al. 2008), loss of NOS2 and NO reduces the effectiveness of the innate immune response against bacteria and virus.
n3:mentions
n4:11165873
Subject Item
_:vb5759474
rdf:type
n3:Context
rdf:value
Since NO-mediated nitrosylation, nitrosation, and nitration of bacterial proteins is an efficient way to kill bacteria (Ogawa et al. 2001; Ren et al. >>2008<<), loss of NOS2 and NO reduces the effectiveness of the innate immune response against bacteria and virus.
n3:mentions
n4:18811727
Subject Item
_:vb5759475
rdf:type
n3:Context
rdf:value
This action of NO is now well described and includes induction of P53, damage to mitochondria, and oxidative and nitrosative damage to multiple cell proteins (Ridnour et al. >>2004<<; Thomas et al. 2008; Wink et al. 1996).
n3:mentions
n4:14977040
Subject Item
_:vb5759476
rdf:type
n3:Context
rdf:value
This action of NO is now well described and includes induction of P53, damage to mitochondria, and oxidative and nitrosative damage to multiple cell proteins (Ridnour et al. 2004; Thomas et al. >>2008<<; Wink et al. 1996).
n3:mentions
n4:18439435
Subject Item
_:vb5759477
rdf:type
n3:Context
rdf:value
This action of NO is now well described and includes induction of P53, damage to mitochondria, and oxidative and nitrosative damage to multiple cell proteins (Ridnour et al. 2004; Thomas et al. 2008; Wink et al. >>1996<<).
n3:mentions
n4:8646847
Subject Item
_:vb5759478
rdf:type
n3:Context
rdf:value
This is due, in part, to the concomitant loss of an endogenous inhibitor that regulates arginase activity, N-OH-arginine, which is formed by an early oxidation step in the conversion of arginine to citrulline (Buga et al. >>1996<<; Morris 2007; Fig.
n3:mentions
n4:8945918
Subject Item
_:vb5759479
rdf:type
n3:Context
rdf:value
This is due, in part, to the concomitant loss of an endogenous inhibitor that regulates arginase activity, N-OH-arginine, which is formed by an early oxidation step in the conversion of arginine to citrulline (Buga et al. 1996; Morris >>2007<<; Fig. 1). In addition, cationic amino acid transporters in the macrophage membrane that supply cells with intracellular arginine are increased in number and activity by LPS stimulation (Closs et al. 2006).
n3:mentions
n4:17513435
Subject Item
_:vb5759480
rdf:type
n3:Context
rdf:value
In addition, cationic amino acid transporters in the macrophage membrane that supply cells with intracellular arginine are increased in number and activity by LPS stimulation (Closs et al. >>2006<<). Cationic amino acid transporter 2 (CAT2; SLC7A2) expression is significantly increased in both alternatively and classically activated macrophages (Yeramian et al. 2006a, b). CAT1 (SLC7A1), the constitutive form of the
n3:mentions
n4:17417706
Subject Item
_:vb5759481
rdf:type
n3:Context
rdf:value
Cationic amino acid transporter 2 (CAT2; SLC7A2) expression is significantly increased in both alternatively and classically activated macrophages (Yeramian et al. 2006a, b). CAT1 (SLC7A1), the constitutive form of the arginine-selective transporter family, has been reported to be downregulated by TGF-β, insulin, and glucocorticoids in some cell types and upregulated in others (Liu and Hatzoglou 1998;
n3:mentions
n4:16670299 n4:16703566
Subject Item
_:vb5759482
rdf:type
n3:Context
rdf:value
CAT1 (SLC7A1), the constitutive form of the arginine-selective transporter family, has been reported to be downregulated by TGF-β, insulin, and glucocorticoids in some cell types and upregulated in others (Liu and Hatzoglou >>1998<<; Durante et al. 2001).
n3:mentions
n4:9891757
Subject Item
_:vb5759483
rdf:type
n3:Context
rdf:value
the constitutive form of the arginine-selective transporter family, has been reported to be downregulated by TGF-β, insulin, and glucocorticoids in some cell types and upregulated in others (Liu and Hatzoglou 1998; Durante et al. >>2001<<). Both microglia and astrocytes in culture have been shown to express both inducible and constitutive forms of arginine transporters (Czapiga and Colton 2003; Manner et al. 2003).
n3:mentions
n4:11222476
Subject Item
_:vb5759484
rdf:type
n3:Context
rdf:value
Both microglia and astrocytes in culture have been shown to express both inducible and constitutive forms of arginine transporters (Czapiga and Colton >>2003<<; Manner et al. 2003).
n3:mentions
n4:12507771
Subject Item
_:vb5759485
rdf:type
n3:Context
rdf:value
Both microglia and astrocytes in culture have been shown to express both inducible and constitutive forms of arginine transporters (Czapiga and Colton 2003; Manner et al. >>2003<<). Furthermore, our laboratory has shown that arginine transport by cultured microglia can be modified by APOE genotype, such that arginine uptake is greater in APOE4/4 microglia compared to microglia cultured from APOE3/3 mice (Czapiga
n3:mentions
n4:12675924
Subject Item
_:vb5759486
rdf:type
n3:Context
rdf:value
our laboratory has shown that arginine transport by cultured microglia can be modified by APOE genotype, such that arginine uptake is greater in APOE4/4 microglia compared to microglia cultured from APOE3/3 mice (Czapiga and Colton >>2003<<).
n3:mentions
n4:12507771
Subject Item
_:vb5759487
rdf:type
n2:Section
dc:title
extracellular matrix and alternative activation of microglia
n2:contains
_:vb5759504 _:vb5759505 _:vb5759506 _:vb5759507 _:vb5759508 _:vb5759509 _:vb5759510 _:vb5759496 _:vb5759497 _:vb5759498 _:vb5759499 _:vb5759500 _:vb5759501 _:vb5759502 _:vb5759503 _:vb5759488 _:vb5759489 _:vb5759490 _:vb5759491 _:vb5759492 _:vb5759493 _:vb5759494 _:vb5759495
Subject Item
_:vb5759488
rdf:type
n3:Context
rdf:value
Components of the ECM have the capacity to regulate the activation state of macrophages and microglia and bind to the same PRRs that are used by pathogens (Morwood and Nicholson >>2006<<). ECM is composed of three types of proteins, which include both protein-bound and unbound glycosaminoglycans (known as proteoglycan and hyaluron, respectively), fibrous proteins (e.g., collagens), and proteins that provide elasticity to
n3:mentions
n4:17122884
Subject Item
_:vb5759489
rdf:type
n3:Context
rdf:value
brain is lower than in other tissues, and its distribution is restricted to special locations in the adult brain that include the basement membranes around the cerebrovasculature, the dura mater, and leptomeninges (Busch and Silver >>2007<<; Galtrey and Fawcett 2007; Morwood and Nicholson 2006). The most abundant proteins in the brain’s ECM are GAGs, particularly hyaluronan, which is composed of a protein core with repeating units of disaccharides.
n3:mentions
n4:17223033
Subject Item
_:vb5759490
rdf:type
n3:Context
rdf:value
other tissues, and its distribution is restricted to special locations in the adult brain that include the basement membranes around the cerebrovasculature, the dura mater, and leptomeninges (Busch and Silver 2007; Galtrey and Fawcett >>2007<<; Morwood and Nicholson 2006). The most abundant proteins in the brain’s ECM are GAGs, particularly hyaluronan, which is composed of a protein core with repeating units of disaccharides.
n3:mentions
n4:17222456
Subject Item
_:vb5759491
rdf:type
n3:Context
rdf:value
is restricted to special locations in the adult brain that include the basement membranes around the cerebrovasculature, the dura mater, and leptomeninges (Busch and Silver 2007; Galtrey and Fawcett 2007; Morwood and Nicholson >>2006<<). The most abundant proteins in the brain’s ECM are GAGs, particularly hyaluronan, which is composed of a protein core with repeating units of disaccharides.
n3:mentions
n4:17122884
Subject Item
_:vb5759492
rdf:type
n3:Context
rdf:value
Cross-linked hyaluronan serves as a backbone for the perineuronal net that surrounds neurons in specific brain regions (Galtrey and Fawcett >>2007<<).
n3:mentions
n4:17222456
Subject Item
_:vb5759493
rdf:type
n3:Context
rdf:value
Although generally not considered as a major factor in the innate immune response, ECM-based ligands in all tissues can both upregulate and downregulate immune signaling (Morwood and Nicholson >>2006<<; Taylor and Gallo 2006).
n3:mentions
n4:17122884
Subject Item
_:vb5759494
rdf:type
n3:Context
rdf:value
Although generally not considered as a major factor in the innate immune response, ECM-based ligands in all tissues can both upregulate and downregulate immune signaling (Morwood and Nicholson 2006; Taylor and Gallo >>2006<<). Ebert et al. (2008) have shown that treatment of BV2 or primary microglia with varying concentrations of CSPG-DS (a disaccharide degradation product of chondroitin sulfate proteoglycan) blocked IFN-γ-mediated NO production and increased
n3:mentions
n4:16394262
Subject Item
_:vb5759495
rdf:type
n3:Context
rdf:value
Ebert et al. (>>2008<<) have shown that treatment of BV2 or primary microglia with varying concentrations of CSPG-DS (a disaccharide degradation product of chondroitin sulfate proteoglycan) blocked IFN-γ-mediated NO production and increased phagocytosis of
n3:mentions
n4:18550791
Subject Item
_:vb5759496
rdf:type
n3:Context
rdf:value
Two genes that can be used to characterize the alternative activation state, FIZZ1 and YM1, are associated with reconstruction of extracellular matrix (Raes et al. 2002a, b). FIZZ1 encodes a 9.4-kDa cysteine-rich protein that is induced by IL-4, IL-13, and IL-21, a newly described cytokine that shares significant homology with IL-4 (Colton et al. 2006a; Raes et al. 2005; Stutz et al. 2003). FIZZ1 (also
n3:mentions
n4:11927645
Subject Item
_:vb5759497
rdf:type
n3:Context
rdf:value
Two genes that can be used to characterize the alternative activation state, FIZZ1 and YM1, are associated with reconstruction of extracellular matrix (Raes et al. 2002a, b). FIZZ1 encodes a 9.4-kDa cysteine-rich protein that is induced by IL-4, IL-13, and IL-21, a newly described cytokine that shares significant homology with IL-4 (Colton et al. 2006a; Raes et al. 2005; Stutz et al. 2003). FIZZ1 (also known
n3:mentions
n4:12892049
Subject Item
_:vb5759498
rdf:type
n3:Context
rdf:value
FIZZ1 encodes a 9.4-kDa cysteine-rich protein that is induced by IL-4, IL-13, and IL-21, a newly described cytokine that shares significant homology with IL-4 (Colton et al. 2006a; Raes et al. 2005; Stutz et al. 2003).
n3:mentions
n4:17005052
Subject Item
_:vb5759499
rdf:type
n3:Context
rdf:value
FIZZ1 encodes a 9.4-kDa cysteine-rich protein that is induced by IL-4, IL-13, and IL-21, a newly described cytokine that shares significant homology with IL-4 (Colton et al. 2006a; Raes et al. >>2005<<; Stutz et al. 2003).
n3:mentions
n4:15591125
Subject Item
_:vb5759500
rdf:type
n3:Context
rdf:value
FIZZ1 encodes a 9.4-kDa cysteine-rich protein that is induced by IL-4, IL-13, and IL-21, a newly described cytokine that shares significant homology with IL-4 (Colton et al. 2006a; Raes et al. 2005; Stutz et al. >>2003<<). FIZZ1 (also known as RELM-A) is a member of a family of resistin-like molecules (RELM) and increases collagen expression and myofibroblast differentiation (Liu et al. 2004). It has also been linked to an interaction between NGF and
n3:mentions
n4:12574343
Subject Item
_:vb5759501
rdf:type
n3:Context
rdf:value
FIZZ1 (also known as RELM-A) is a member of a family of resistin-like molecules (RELM) and increases collagen expression and myofibroblast differentiation (Liu et al. >>2004<<). It has also been linked to an interaction between NGF and neurons in the lung, but its role in the CNS injury response is unknown.
n3:mentions
n4:15039219
Subject Item
_:vb5759502
rdf:type
n3:Context
rdf:value
Ym1 (Chi3-L3) is a novel mammalian lectin that was discovered as a secretory product of mouse peritoneal macrophages in response to nematode infections (Hung et al. >>2002<<). However, multiple tissues including the brain express Ym1 during an immune response.
n3:mentions
n4:12101265
Subject Item
_:vb5759503
rdf:type
n3:Context
rdf:value
For example, Ym1 expression was transiently induced in microglia over 3 days and was gone by day 6 after a stab wound (Hung et al. >>2002<<). Our studies have shown that Ym1 mRNA increases in IL-4- or IL-13-stimulated BV2 cells in vitro (Colton et al. 2006a). The functions of Ym1 are not well known but are believed to involve its ability to bind heparin sulfate. Heparin
n3:mentions
n4:12101265
Subject Item
_:vb5759504
rdf:type
n3:Context
rdf:value
Our studies have shown that Ym1 mRNA increases in IL-4- or IL-13-stimulated BV2 cells in vitro (Colton et al. 2006a). The functions of Ym1 are not well known but are believed to involve its ability to bind heparin sulfate. Heparin sulfate serves as a docking site for growth factors in the ECM and is degraded by heparinases during inflammation. By
n3:mentions
n4:17005052
Subject Item
_:vb5759505
rdf:type
n3:Context
rdf:value
By binding to heparin, Ym1 is believed to slow the loss of growth factors that may be required for rebuilding of the tissue (Raes et al. 2002a). Direct human homologs have not been identified for Ym1, but two closely related genes, CHI3L1 and CHI3L2, are found in human tissues including the brain (Colton et al. 2006a; Rehli et al. 1997). CHI3L1 (also known as HC-gp 39 or YKL-40)
n3:mentions
n4:11927645
Subject Item
_:vb5759506
rdf:type
n3:Context
rdf:value
Direct human homologs have not been identified for Ym1, but two closely related genes, CHI3L1 and CHI3L2, are found in human tissues including the brain (Colton et al. 2006a; Rehli et al. 1997).
n3:mentions
n4:17005052
Subject Item
_:vb5759507
rdf:type
n3:Context
rdf:value
Direct human homologs have not been identified for Ym1, but two closely related genes, CHI3L1 and CHI3L2, are found in human tissues including the brain (Colton et al. 2006a; Rehli et al. >>1997<<). CHI3L1 (also known as HC-gp 39 or YKL-40) and its close homolog, CHI3L2 (YKL-39), are members of a large family of human chitinases that are nonhydrolytic and thus do not function as enzymes (Rehli et al. 1997). CHI3L1 and 2 are
n3:mentions
n4:9244440
Subject Item
_:vb5759508
rdf:type
n3:Context
rdf:value
CHI3L1 (also known as HC-gp 39 or YKL-40) and its close homolog, CHI3L2 (YKL-39), are members of a large family of human chitinases that are nonhydrolytic and thus do not function as enzymes (Rehli et al. >>1997<<). CHI3L1 and 2 are produced by macrophages and are induced during an alternative activation state where they are believed to participate in reconstruction of ECM (Recklies et al. 2002). In brain, CHI3L1 is a characteristic marker of
n3:mentions
n4:9244440
Subject Item
_:vb5759509
rdf:type
n3:Context
rdf:value
CHI3L1 and 2 are produced by macrophages and are induced during an alternative activation state where they are believed to participate in reconstruction of ECM (Recklies et al. >>2002<<). In brain, CHI3L1 is a characteristic marker of glioblastoma (Junker et al. 2005), suggesting that glial tumors, similar to some cancers in the periphery, may be associated with alternatively activated macrophages.
n3:mentions
n4:12071845
Subject Item
_:vb5759510
rdf:type
n3:Context
rdf:value
In brain, CHI3L1 is a characteristic marker of glioblastoma (Junker et al. >>2005<<), suggesting that glial tumors, similar to some cancers in the periphery, may be associated with alternatively activated macrophages.
n3:mentions
n4:15771622
Subject Item
_:vb5759511
rdf:type
n2:Section
dc:title
alternative activation and phagocytosis
n2:contains
_:vb5759520 _:vb5759512 _:vb5759513 _:vb5759514 _:vb5759515 _:vb5759516 _:vb5759517 _:vb5759518 _:vb5759519
Subject Item
_:vb5759512
rdf:type
n3:Context
rdf:value
For example, FcRI, FcRII, and CD163 expression levels are reduced by IL-4 while MR, complement receptor 3, and dectin 1 are increased (Gordon >>2003<<; Nimmerjahn and Ravetch 2006;Schaer et al. 2002; Willment et al. 2003).
n3:mentions
n4:12511873
Subject Item
_:vb5759513
rdf:type
n3:Context
rdf:value
For example, FcRI, FcRII, and CD163 expression levels are reduced by IL-4 while MR, complement receptor 3, and dectin 1 are increased (Gordon 2003; Nimmerjahn and Ravetch >>2006<<;Schaer et al. 2002; Willment et al. 2003).
n3:mentions
n4:16413920
Subject Item
_:vb5759514
rdf:type
n3:Context
rdf:value
For example, FcRI, FcRII, and CD163 expression levels are reduced by IL-4 while MR, complement receptor 3, and dectin 1 are increased (Gordon 2003; Nimmerjahn and Ravetch 2006;Schaer et al. >>2002<<; Willment et al. 2003).
n3:mentions
n4:12358930
Subject Item
_:vb5759515
rdf:type
n3:Context
rdf:value
For example, FcRI, FcRII, and CD163 expression levels are reduced by IL-4 while MR, complement receptor 3, and dectin 1 are increased (Gordon 2003; Nimmerjahn and Ravetch 2006;Schaer et al. 2002; Willment et al. >>2003<<). Costimulatory factors also affect the level of phagocytosis observed in alternatively activated macrophages. Gratchev et al. (2005) have shown that IL-4-treated peripheral macrophages increase phagocytosis of latex beads compared to
n3:mentions
n4:14568930
Subject Item
_:vb5759516
rdf:type
n3:Context
rdf:value
Gratchev et al. (>>2005<<) have shown that IL-4-treated peripheral macrophages increase phagocytosis of latex beads compared to IFN-γ treatment, which does not promote phagocytosis.
n3:mentions
n4:15644118
Subject Item
_:vb5759517
rdf:type
n3:Context
rdf:value
However, IL-4 in combination with other cytoactive factors such as colony-stimulating factor (CSF) or glucocorticoids (dexamethasone) reduces particle uptake (Gratchev et al. >>2005<<; Leidi et al. 2009).
n3:mentions
n4:15644118
Subject Item
_:vb5759518
rdf:type
n3:Context
rdf:value
However, IL-4 in combination with other cytoactive factors such as colony-stimulating factor (CSF) or glucocorticoids (dexamethasone) reduces particle uptake (Gratchev et al. 2005; Leidi et al. >>2009<<). The reduction of phagocytosis when IL-4 and dexamethasone are both present is surprising since glucocorticoids dramatically increase phagocytosis. Thus, IL-4 can apparently bypass glucocorticoid’s actions on phagocytosis. While the
n3:mentions
n4:19299742
Subject Item
_:vb5759519
rdf:type
n3:Context
rdf:value
Glucocorticoid-mediated stimulation of phagocytosis is due, in part, to increased expression of MARCO, a scavenger receptor from the SR-A family (Taylor et al. 2005b). Although constitutive expression has been found in some tissues, MARCO is also highly upregulated by activation of TLRs and by treatment with IFN-γ and is thus associated with classical activation. Simultaneous treatment of IL-4 plus
n3:mentions
n4:15771589
Subject Item
_:vb5759520
rdf:type
n3:Context
rdf:value
Simultaneous treatment of IL-4 plus dexamethasone reduced MARCO expression but not back to the levels observed in macrophages treated with IL-4 alone (Gratchev et al. >>2005<<). Equivalent studies have not yet been done on microglia but are extremely important to understanding how alternative activation can affect uptake and removal of pathogens such as amyloid deposits in the brain.
n3:mentions
n4:15644118
Subject Item
_:vb5759521
rdf:type
n2:Section
dc:title
uptake of apoptotic cells
n2:contains
_:vb5759522 _:vb5759523 _:vb5759524 _:vb5759525 _:vb5759526 _:vb5759527 _:vb5759528 _:vb5759529 _:vb5759530 _:vb5759531 _:vb5759532 _:vb5759533 _:vb5759534 _:vb5759535 _:vb5759536 _:vb5759537
Subject Item
_:vb5759522
rdf:type
n3:Context
rdf:value
As noted by Erwig and Henson (>>2007<<), this is a misnomer in both cases.
n3:mentions
n4:17591947
Subject Item
_:vb5759523
rdf:type
n3:Context
rdf:value
via Fc receptors, complement receptors, or lectins results in production of proinflammatory cytokines and can be proinflammatory (i.e., “immunogenic”), pathogen uptake via Fc receptors can also inhibit inflammation (Crocker et al. >>2007<<; Hamerman and Lanier 2006; Long 2008; Underhill and Goodridge 2007; van Lookeren Campagne et al. 2007).
n3:mentions
n4:17380156
Subject Item
_:vb5759524
rdf:type
n3:Context
rdf:value
receptors, or lectins results in production of proinflammatory cytokines and can be proinflammatory (i.e., “immunogenic”), pathogen uptake via Fc receptors can also inhibit inflammation (Crocker et al. 2007; Hamerman and Lanier >>2006<<; Long 2008; Underhill and Goodridge 2007; van Lookeren Campagne et al. 2007).
n3:mentions
n4:16449667
Subject Item
_:vb5759525
rdf:type
n3:Context
rdf:value
or lectins results in production of proinflammatory cytokines and can be proinflammatory (i.e., “immunogenic”), pathogen uptake via Fc receptors can also inhibit inflammation (Crocker et al. 2007; Hamerman and Lanier 2006; Long >>2008<<; Underhill and Goodridge 2007; van Lookeren Campagne et al. 2007). Likewise, the term “nonimmunogenic” implies a neutral or static effect on inflammation when, in fact, apoptotic cell uptake strongly downregulates macrophage activity.
n3:mentions
n4:18759921
Subject Item
_:vb5759526
rdf:type
n3:Context
rdf:value
of proinflammatory cytokines and can be proinflammatory (i.e., “immunogenic”), pathogen uptake via Fc receptors can also inhibit inflammation (Crocker et al. 2007; Hamerman and Lanier 2006; Long 2008; Underhill and Goodridge >>2007<<; van Lookeren Campagne et al. 2007). Likewise, the term “nonimmunogenic” implies a neutral or static effect on inflammation when, in fact, apoptotic cell uptake strongly downregulates macrophage activity.
n3:mentions
n4:17197236
Subject Item
_:vb5759527
rdf:type
n3:Context
rdf:value
and can be proinflammatory (i.e., “immunogenic”), pathogen uptake via Fc receptors can also inhibit inflammation (Crocker et al. 2007; Hamerman and Lanier 2006; Long 2008; Underhill and Goodridge 2007; van Lookeren Campagne et al. >>2007<<). Likewise, the term “nonimmunogenic” implies a neutral or static effect on inflammation when, in fact, apoptotic cell uptake strongly downregulates macrophage activity.
n3:mentions
n4:17590164
Subject Item
_:vb5759528
rdf:type
n3:Context
rdf:value
The removal of apoptotic cells in the brain is the primary job of microglia although other cell types, most commonly astrocytes, contribute to clearance (Griffiths et al. >>2009<<). While macrophages express a wide variety of receptors that detect which dying cell is destined for uptake, cells undergoing apoptosis signal loss of viability by a sparse repertoire of mechanisms.
n3:mentions
n4:19225414
Subject Item
_:vb5759529
rdf:type
n3:Context
rdf:value
2, apoptotic cells are primarily identified by redistribution of phosphatidylserine (PS) to the surface membrane and the appearance of calreticulin (CRT) on the cell surface (Gardai et al. >>2005<<; Gregory and Devitt 2004; Hume 2008; Wu et al. 2006).
n3:mentions
n4:16239148
Subject Item
_:vb5759530
rdf:type
n3:Context
rdf:value
2, apoptotic cells are primarily identified by redistribution of phosphatidylserine (PS) to the surface membrane and the appearance of calreticulin (CRT) on the cell surface (Gardai et al. 2005; Gregory and Devitt >>2004<<; Hume 2008; Wu et al. 2006).
n3:mentions
n4:15312130
Subject Item
_:vb5759531
rdf:type
n3:Context
rdf:value
2, apoptotic cells are primarily identified by redistribution of phosphatidylserine (PS) to the surface membrane and the appearance of calreticulin (CRT) on the cell surface (Gardai et al. 2005; Gregory and Devitt 2004; Hume >>2008<<; Wu et al. 2006).
n3:mentions
n4:18087250
Subject Item
_:vb5759532
rdf:type
n3:Context
rdf:value
cells are primarily identified by redistribution of phosphatidylserine (PS) to the surface membrane and the appearance of calreticulin (CRT) on the cell surface (Gardai et al. 2005; Gregory and Devitt 2004; Hume 2008; Wu et al. >>2006<<). In some cases, complement component, C1q, binding to membrane blebs on apoptotic cells may also serve as a signal to phagocytes (Maderna and Godson 2003).
n3:mentions
n4:16529932
Subject Item
_:vb5759533
rdf:type
n3:Context
rdf:value
In some cases, complement component, C1q, binding to membrane blebs on apoptotic cells may also serve as a signal to phagocytes (Maderna and Godson >>2003<<). Microglia and other macrophages express PS receptors that bind directly to PS on the apoptotic cell and initiate phagocytosis. Alternatively, macrophages produce and secrete specialized linker (adaptor) proteins that are also called
n3:mentions
n4:14636945
Subject Item
_:vb5759534
rdf:type
n3:Context
rdf:value
Grommes et al. (>>2008<<) have recently described the role of one of the linker proteins, growth arrest specific 6 (GAS-6), in microglial phagocytosis.
n3:mentions
n4:18247125
Subject Item
_:vb5759535
rdf:type
n3:Context
rdf:value
Fuller and Van Eldik (>>2008<<) have shown that dominant negative forms of MFG-E8 block phagocytosis, suggesting an integral role for MFG-E8 in the multistep uptake of apoptotic neurons by microglia.
n3:mentions
n4:18670887
Subject Item
_:vb5759536
rdf:type
n3:Context
rdf:value
Immunosuppression has also been demonstrated in microglia by Minghetti and Pocchiari (>>2007<<) who have shown that exposure of cultured microglia to either apoptotic cells or to phosphotidyl serine-laden liposomes decreased TNF-α and NOS2 mRNA and their gene products.
n3:mentions
n4:17678966
Subject Item
_:vb5759537
rdf:type
n3:Context
rdf:value
Potential mechanisms for this immunosuppression of macrophage function have been reviewed by Birge and Ucker (>>2008<<). Fig.
n3:mentions
n4:18451871
Subject Item
_:vb5759538
rdf:type
n2:Section
dc:title
tgf-β and il-10 in acquired deactivation
n2:contains
_:vb5759548 _:vb5759549 _:vb5759550 _:vb5759551 _:vb5759544 _:vb5759545 _:vb5759546 _:vb5759547 _:vb5759540 _:vb5759541 _:vb5759542 _:vb5759543 _:vb5759539 _:vb5759564 _:vb5759565 _:vb5759566 _:vb5759567 _:vb5759560 _:vb5759561 _:vb5759562 _:vb5759563 _:vb5759556 _:vb5759557 _:vb5759558 _:vb5759559 _:vb5759552 _:vb5759553 _:vb5759554 _:vb5759555 _:vb5759568 _:vb5759569 _:vb5759570
Subject Item
_:vb5759539
rdf:type
n3:Context
rdf:value
TGF-β and IL-10 are known induction agents for acquired deactivation and are released by multiple cell types in the brain including astrocytes (Fadok et al. >>1998<<; Finch et al. 1993; Pratt and McPherson 1997).
n3:mentions
n4:9466984
Subject Item
_:vb5759540
rdf:type
n3:Context
rdf:value
TGF-β and IL-10 are known induction agents for acquired deactivation and are released by multiple cell types in the brain including astrocytes (Fadok et al. 1998; Finch et al. >>1993<<; Pratt and McPherson 1997). Microglia are a major source of brain TGF-β and uptake of apoptotic cells increases the production and release of both TGF-β and IL-10 by microglia (De Simone et al. 2004; Minghetti et al. 2005).
n3:mentions
n4:8300749
Subject Item
_:vb5759541
rdf:type
n3:Context
rdf:value
TGF-β and IL-10 are known induction agents for acquired deactivation and are released by multiple cell types in the brain including astrocytes (Fadok et al. 1998; Finch et al. 1993; Pratt and McPherson >>1997<<). Microglia are a major source of brain TGF-β and uptake of apoptotic cells increases the production and release of both TGF-β and IL-10 by microglia (De Simone et al. 2004; Minghetti et al. 2005).
n3:mentions
n4:9620642
Subject Item
_:vb5759542
rdf:type
n3:Context
rdf:value
Microglia are a major source of brain TGF-β and uptake of apoptotic cells increases the production and release of both TGF-β and IL-10 by microglia (De Simone et al. >>2004<<; Minghetti et al. 2005).
n3:mentions
n4:15126686
Subject Item
_:vb5759543
rdf:type
n3:Context
rdf:value
Microglia are a major source of brain TGF-β and uptake of apoptotic cells increases the production and release of both TGF-β and IL-10 by microglia (De Simone et al. 2004; Minghetti et al. >>2005<<). In addition to these anti-inflammatory cytokines, treatment of microglia with apoptotic cells increases mRNA and protein levels for prostaglandin E2, cyclooxygenase 2, and NGF (Minghetti and Pocchiari 2007). Xiao et al. (2008) have
n3:mentions
n4:15850664
Subject Item
_:vb5759544
rdf:type
n3:Context
rdf:value
In addition to these anti-inflammatory cytokines, treatment of microglia with apoptotic cells increases mRNA and protein levels for prostaglandin E2, cyclooxygenase 2, and NGF (Minghetti and Pocchiari >>2007<<). Xiao et al. (2008) have further shown in macrophage cell lines that contact with apoptotic cells increases translation and transcription of TGF-β. Both TGF-β and IL-10 inhibit immune-stimulated IL-1β, IL-6, IL-12, IL-18, and TNF-α
n3:mentions
n4:17678966
Subject Item
_:vb5759545
rdf:type
n3:Context
rdf:value
Xiao et al. (>>2008<<) have further shown in macrophage cell lines that contact with apoptotic cells increases translation and transcription of TGF-β.
n3:mentions
n4:18714031
Subject Item
_:vb5759546
rdf:type
n3:Context
rdf:value
Both TGF-β and IL-10 inhibit immune-stimulated IL-1β, IL-6, IL-12, IL-18, and TNF-α production, decrease levels of chemokines, and decrease expression of MHC II and its costimulatory proteins (Fadok et al. >>1998<<; Lodge and Sriram 1996; Martinez et al. 2008; Minghetti et al. 2005; Takahashi et al. 2005; Wei and Jonakait 1999).
n3:mentions
n4:9466984
Subject Item
_:vb5759547
rdf:type
n3:Context
rdf:value
Both TGF-β and IL-10 inhibit immune-stimulated IL-1β, IL-6, IL-12, IL-18, and TNF-α production, decrease levels of chemokines, and decrease expression of MHC II and its costimulatory proteins (Fadok et al. 1998; Lodge and Sriram >>1996<<; Martinez et al. 2008; Minghetti et al. 2005; Takahashi et al. 2005; Wei and Jonakait 1999).
n3:mentions
n4:8864135
Subject Item
_:vb5759548
rdf:type
n3:Context
rdf:value
inhibit immune-stimulated IL-1β, IL-6, IL-12, IL-18, and TNF-α production, decrease levels of chemokines, and decrease expression of MHC II and its costimulatory proteins (Fadok et al. 1998; Lodge and Sriram 1996; Martinez et al. >>2008<<; Minghetti et al. 2005; Takahashi et al. 2005; Wei and Jonakait 1999).
n3:mentions
n4:17981560
Subject Item
_:vb5759549
rdf:type
n3:Context
rdf:value
IL-1β, IL-6, IL-12, IL-18, and TNF-α production, decrease levels of chemokines, and decrease expression of MHC II and its costimulatory proteins (Fadok et al. 1998; Lodge and Sriram 1996; Martinez et al. 2008; Minghetti et al. >>2005<<; Takahashi et al. 2005; Wei and Jonakait 1999).
n3:mentions
n4:15850664
Subject Item
_:vb5759550
rdf:type
n3:Context
rdf:value
IL-18, and TNF-α production, decrease levels of chemokines, and decrease expression of MHC II and its costimulatory proteins (Fadok et al. 1998; Lodge and Sriram 1996; Martinez et al. 2008; Minghetti et al. 2005; Takahashi et al. >>2005<<; Wei and Jonakait 1999).
n3:mentions
n4:15728241
Subject Item
_:vb5759551
rdf:type
n3:Context
rdf:value
decrease levels of chemokines, and decrease expression of MHC II and its costimulatory proteins (Fadok et al. 1998; Lodge and Sriram 1996; Martinez et al. 2008; Minghetti et al. 2005; Takahashi et al. 2005; Wei and Jonakait >>1999<<). IL-10 and TGF-β have growth factor properties and promote survival of neurons or other cells via actions on Bcl2 and Bcl-XL (Finch et al. 1993; Kiefer et al. 1995; Vivien and Ali 2006; Weis et al. 2009; Zocchia et al. 1997).
n3:mentions
n4:10229111
Subject Item
_:vb5759552
rdf:type
n3:Context
rdf:value
IL-10 and TGF-β have growth factor properties and promote survival of neurons or other cells via actions on Bcl2 and Bcl-XL (Finch et al. >>1993<<; Kiefer et al. 1995; Vivien and Ali 2006; Weis et al. 2009; Zocchia et al. 1997).
n3:mentions
n4:8300749
Subject Item
_:vb5759553
rdf:type
n3:Context
rdf:value
IL-10 and TGF-β have growth factor properties and promote survival of neurons or other cells via actions on Bcl2 and Bcl-XL (Finch et al. 1993; Kiefer et al. >>1995<<; Vivien and Ali 2006; Weis et al. 2009; Zocchia et al. 1997).
n3:mentions
n4:7572285
Subject Item
_:vb5759554
rdf:type
n3:Context
rdf:value
IL-10 and TGF-β have growth factor properties and promote survival of neurons or other cells via actions on Bcl2 and Bcl-XL (Finch et al. 1993; Kiefer et al. 1995; Vivien and Ali >>2006<<; Weis et al. 2009; Zocchia et al. 1997).
n3:mentions
n4:16271500
Subject Item
_:vb5759555
rdf:type
n3:Context
rdf:value
IL-10 and TGF-β have growth factor properties and promote survival of neurons or other cells via actions on Bcl2 and Bcl-XL (Finch et al. 1993; Kiefer et al. 1995; Vivien and Ali 2006; Weis et al. >>2009<<; Zocchia et al. 1997).
n3:mentions
n4:19129475
Subject Item
_:vb5759556
rdf:type
n3:Context
rdf:value
IL-10 and TGF-β have growth factor properties and promote survival of neurons or other cells via actions on Bcl2 and Bcl-XL (Finch et al. 1993; Kiefer et al. 1995; Vivien and Ali 2006; Weis et al. 2009; Zocchia et al. >>1997<<). Additionally, TGF-β and IL-10 both affect the cerebrovasculature by increasing tight junctions at the blood–brain barrier (Oshima et al. 2001; Ronaldson et al. 2009; Wu et al. 2008). In adult mice, TGF-β knockout leads to vascular
n3:mentions
n4:9106258
Subject Item
_:vb5759557
rdf:type
n3:Context
rdf:value
Additionally, TGF-β and IL-10 both affect the cerebrovasculature by increasing tight junctions at the blood–brain barrier (Oshima et al. >>2001<<; Ronaldson et al. 2009; Wu et al. 2008).
n3:mentions
n4:11162203
Subject Item
_:vb5759558
rdf:type
n3:Context
rdf:value
Additionally, TGF-β and IL-10 both affect the cerebrovasculature by increasing tight junctions at the blood–brain barrier (Oshima et al. 2001; Ronaldson et al. >>2009<<; Wu et al. 2008).
n3:mentions
n4:19319146
Subject Item
_:vb5759559
rdf:type
n3:Context
rdf:value
Additionally, TGF-β and IL-10 both affect the cerebrovasculature by increasing tight junctions at the blood–brain barrier (Oshima et al. 2001; Ronaldson et al. 2009; Wu et al. >>2008<<). In adult mice, TGF-β knockout leads to vascular defects and loss of brain–blood barrier integrity (Basu et al. 2002). Makwana et al. (2007) showed that MHCII expression and the number of perivascular microglia significantly increased in
n3:mentions
n4:18848892
Subject Item
_:vb5759560
rdf:type
n3:Context
rdf:value
In adult mice, TGF-β knockout leads to vascular defects and loss of brain–blood barrier integrity (Basu et al. >>2002<<). Makwana et al. (2007) showed that MHCII expression and the number of perivascular microglia significantly increased in TGF-β-deficient mice. However, the resulting localized proinflammatory state was not associated with increased
n3:mentions
n4:12237848
Subject Item
_:vb5759561
rdf:type
n3:Context
rdf:value
Makwana et al. (>>2007<<) showed that MHCII expression and the number of perivascular microglia significantly increased in TGF-β-deficient mice.
n3:mentions
n4:17942715
Subject Item
_:vb5759562
rdf:type
n3:Context
rdf:value
Exposure to IL-10 increases the expression of IL-4Rα, a receptor variant for IL-4 and IL-13, thus increasing the sensitivity of the macrophage for these alternative activation stimuli (Andrews et al. >>2006<<). As a result, the combination of IL-4 and IL-10 acts synergistically to alter macrophage function. Lang et al. (2002) have shown that arginase 1 mRNA and protein expression by macrophages is increased by IL-4 treatment but dramatically
n3:mentions
n4:16751391
Subject Item
_:vb5759563
rdf:type
n3:Context
rdf:value
Lang et al. (>>2002<<) have shown that arginase 1 mRNA and protein expression by macrophages is increased by IL-4 treatment but dramatically increases more when both IL-10 and IL-4 are present than IL-4 alone.
n3:mentions
n4:12193690
Subject Item
_:vb5759564
rdf:type
n3:Context
rdf:value
IL-10’s protective effects are mediated, in part, by heme oxygenase 1 (HO-1; Lee and Chau >>2002<<; Weis et al. 2009).
n3:mentions
n4:11875494
Subject Item
_:vb5759565
rdf:type
n3:Context
rdf:value
IL-10’s protective effects are mediated, in part, by heme oxygenase 1 (HO-1; Lee and Chau 2002; Weis et al. >>2009<<). HO-1 catalyzes the degradation of intracellular heme-containing proteins to produce carbon monoxide and bilirubin/biliverdin. HO-1 activation has been shown to provide strong antiapoptotic actions (Weis et al. 2009). Importantly, the
n3:mentions
n4:19129475
Subject Item
_:vb5759566
rdf:type
n3:Context
rdf:value
HO-1 activation has been shown to provide strong antiapoptotic actions (Weis et al. >>2009<<). Importantly, the mechanisms by which TGF-β and IL-10 achieve immunosuppression are different. Immunosuppression by IL-10 requires STAT3 and macrophages from STAT3-deficient mice fail to respond to IL-10 (Lang et al. 2002) while TGF-β
n3:mentions
n4:19129475
Subject Item
_:vb5759567
rdf:type
n3:Context
rdf:value
Immunosuppression by IL-10 requires STAT3 and macrophages from STAT3-deficient mice fail to respond to IL-10 (Lang et al. >>2002<<) while TGF-β signaling is mediated by both Smad-dependent and Smad-independent pathways (Li et al. 2006).
n3:mentions
n4:12193690
Subject Item
_:vb5759568
rdf:type
n3:Context
rdf:value
Immunosuppression by IL-10 requires STAT3 and macrophages from STAT3-deficient mice fail to respond to IL-10 (Lang et al. 2002) while TGF-β signaling is mediated by both Smad-dependent and Smad-independent pathways (Li et al. >>2006<<). The signaling pathways involved in TGF-β-mediated immunosuppression have been extensively reviewed by Li et al. (2006) and for IL-10 by Mosser and Zhang (2008).
n3:mentions
n4:16551245
Subject Item
_:vb5759569
rdf:type
n3:Context
rdf:value
The signaling pathways involved in TGF-β-mediated immunosuppression have been extensively reviewed by Li et al. (>>2006<<) and for IL-10 by Mosser and Zhang (2008).
n3:mentions
n4:16551245
Subject Item
_:vb5759570
rdf:type
n3:Context
rdf:value
The signaling pathways involved in TGF-β-mediated immunosuppression have been extensively reviewed by Li et al. (2006) and for IL-10 by Mosser and Zhang (>>2008<<).
n3:mentions
n4:19161426
Subject Item
_:vb5759571
rdf:type
n2:Section
dc:title
apoptotic cell uptake and sphingosine 1 phosphate kinase
n2:contains
_:vb5759576 _:vb5759577 _:vb5759578 _:vb5759572 _:vb5759573 _:vb5759574 _:vb5759575
Subject Item
_:vb5759572
rdf:type
n3:Context
rdf:value
Recently, sphingosine-1-phosphate (S1P) has been implicated as an endogenous switch for acquired deactivation in macrophages (Weigert et al. >>2007<<). Sphingolipids are ubiquitous components of membranes that can be metabolized into three biologically active components, ceramide, sphingosine, and S1P (Maceyka et al. 2002).
n3:mentions
n4:17652460
Subject Item
_:vb5759573
rdf:type
n3:Context
rdf:value
Sphingolipids are ubiquitous components of membranes that can be metabolized into three biologically active components, ceramide, sphingosine, and S1P (Maceyka et al. >>2002<<). In most cells, the formation of ceramide or sphingosine by activated sphingomyelinases and their accumulation within the cell is linked to induction of apoptosis. In contrast, when ceramide and sphingosine levels are decreased by the
n3:mentions
n4:12531554
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_:vb5759574
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Two isoforms of SphK have been found (Sphk1; SphK2) and both are activated by growth factors and cytokines (Maceyka et al. >>2002<<). Mouse macrophages predominantly express SphK2 while human cells express both. Weigert et al. (2007) have shown that S1P released from apoptotic cells initiates acquired deactivation in macrophages. This effect was not observed in SphK
n3:mentions
n4:12531554
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_:vb5759575
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Weigert et al. (>>2007<<) have shown that S1P released from apoptotic cells initiates acquired deactivation in macrophages.
n3:mentions
n4:17652460
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_:vb5759576
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This effect was not observed in SphK knockout mice and was dependent on S1P receptors (Hughes et al. >>2008<<;Weigert et al. 2007).
n3:mentions
n4:18323526
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_:vb5759577
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This effect was not observed in SphK knockout mice and was dependent on S1P receptors (Hughes et al. 2008;Weigert et al. >>2007<<). Edwards et al. (2006) have also shown that apoptotic cells can induce SphK production within macrophages and has identified this gene family as a marker for the acquired deactivation state.
n3:mentions
n4:17652460
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_:vb5759578
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Edwards et al. (>>2006<<) have also shown that apoptotic cells can induce SphK production within macrophages and has identified this gene family as a marker for the acquired deactivation state.
n3:mentions
n4:16905575
Subject Item
_:vb5759579
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n2:Section
dc:title
alternative activation and acquired deactivation in neurodegenerative disease
n2:contains
_:vb5759616 _:vb5759617 _:vb5759580 _:vb5759581 _:vb5759582 _:vb5759583 _:vb5759592 _:vb5759593 _:vb5759594 _:vb5759595 _:vb5759596 _:vb5759597 _:vb5759598 _:vb5759599 _:vb5759584 _:vb5759585 _:vb5759586 _:vb5759587 _:vb5759588 _:vb5759589 _:vb5759590 _:vb5759591 _:vb5759608 _:vb5759609 _:vb5759610 _:vb5759611 _:vb5759612 _:vb5759613 _:vb5759614 _:vb5759615 _:vb5759600 _:vb5759601 _:vb5759602 _:vb5759603 _:vb5759604 _:vb5759605 _:vb5759606 _:vb5759607
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Wynn et al. (>>2004<<) have defined chronic inflammation as the coexpression of alternative activation and classical activation.
n3:mentions
n4:15361239
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Consequently, a low-grade low-pathology but chronic infection is maintained (Bogdan >>2008<<; Couper et al. 2008; Raes et al. 2007; Wynn et al. 2004).
n3:mentions
n4:18363880
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_:vb5759582
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Consequently, a low-grade low-pathology but chronic infection is maintained (Bogdan 2008; Couper et al. >>2008<<; Raes et al. 2007; Wynn et al. 2004).
n3:mentions
n4:18424693
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_:vb5759583
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Consequently, a low-grade low-pathology but chronic infection is maintained (Bogdan 2008; Couper et al. 2008; Raes et al. >>2007<<; Wynn et al. 2004).
n3:mentions
n4:17628461
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_:vb5759584
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Consequently, a low-grade low-pathology but chronic infection is maintained (Bogdan 2008; Couper et al. 2008; Raes et al. 2007; Wynn et al. >>2004<<). In parasitic diseases such as schistosomiasis, the balance between classical activation and alternative activation/acquired deactivation states is of “benefit” to host and to parasite. The host benefits from reduced self-tissue damage
n3:mentions
n4:15361239
Subject Item
_:vb5759585
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n3:Context
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A detailed list of proteins that interact with Aβ has been provided in the excellent review on AD by Bharadwaj et al. (>>2009<<). In vivo, microglial responses to Aβ show an interesting complexity that might reflect the heterogenous state of microglial activation. For example, in a two-photon imaging study, Meyer-Luehmann et al. (2008) observed the rapid
n3:mentions
n4:19374683
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_:vb5759586
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For example, in a two-photon imaging study, Meyer-Luehmann et al. (>>2008<<) observed the rapid accumulation of microglia at newly born amyloid plaques.
n3:mentions
n4:18256671
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_:vb5759587
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n3:Context
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This in vivo finding was confirmed by Bolmont et al. (>>2008<<) in mice that coexpress mutated human amyloid precursor protein (APP) and mutated human presenilin 1 (PS-1; also called APP/PS1 mice).
n3:mentions
n4:18417708
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_:vb5759588
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n3:Context
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Also, using APP/PS1 mice, Jimenez et al. (>>2008<<) showed that microglia surrounding amyloid plaques in young mice (4–6 months) express some IL-1β immunoreactivity but do not express other typical classical activation markers.
n3:mentions
n4:18987201
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_:vb5759589
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n3:Context
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Maier et al. (>>2008<<) have also shown that complement factor C3 regulates brain IL-4 brain levels in mice expressing the APPsw (K670N, M671L), IN (V717F) transgene.
n3:mentions
n4:18562603
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from APP Tg2576 mouse brain and autopsied brain samples from humans with AD where expression levels for genes characteristic of alternative activation were significantly increased in AD compared to age-matched controls (Colton et al. 2006a). Higher levels were found for arginase 1, chitinase 3-like 1, and chitinase 3-like 2.
n3:mentions
n4:17005052
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_:vb5759591
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n3:Context
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and IL-10 are higher in CSF from humans with prion disease (Creutzfeld-Jacob) and mice models of prion disease also show elevated mRNA and protein levels for TGF-β, associated with depressed levels of NOS2 and IL-1β (Cunningham et al. >>2002<<; Perry et al. 2002; Stoeck et al. 2005).
n3:mentions
n4:11972797
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_:vb5759592
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in CSF from humans with prion disease (Creutzfeld-Jacob) and mice models of prion disease also show elevated mRNA and protein levels for TGF-β, associated with depressed levels of NOS2 and IL-1β (Cunningham et al. 2002; Perry et al. >>2002<<; Stoeck et al. 2005).
n3:mentions
n4:12045736
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_:vb5759593
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with prion disease (Creutzfeld-Jacob) and mice models of prion disease also show elevated mRNA and protein levels for TGF-β, associated with depressed levels of NOS2 and IL-1β (Cunningham et al. 2002; Perry et al. 2002; Stoeck et al. >>2005<<). Table
n3:mentions
n4:16216944
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_:vb5759594
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When activated during an immune response, these receptors work in an additive or synergistic manner to upregulate classical activation (Underhill >>2007<<). We also do not know if microglial activation states are functionally plastic. Once polarized to a specific state, can polarized microglia respond in an appropriate manner to a new incoming signal or to the same signal, repeated? To
n3:mentions
n4:17850483
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_:vb5759595
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To answer these questions, Gratchev et al. (>>2006<<) polarized human monocyte-derived macrophages to a classically activated state and then switched the polarization to alternative activation by treatment with IL-4.
n3:mentions
n4:16920487
Subject Item
_:vb5759596
rdf:type
n3:Context
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Age also affects microglial polarization and function (Conde and Streit >>2006<<). Jimenez et al. (2008) have shown that microglia from 18-month-old APP/PS1 mice increased expression of TNF-α mRNA and protein (classical activation) while IL-4 and Ym-1 expression (alternative activation) decreased compared to young
n3:mentions
n4:16651881
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_:vb5759597
rdf:type
n3:Context
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Jimenez et al. (>>2008<<) have shown that microglia from 18-month-old APP/PS1 mice increased expression of TNF-α mRNA and protein (classical activation) while IL-4 and Ym-1 expression (alternative activation) decreased compared to young mice.
n3:mentions
n4:18987201
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_:vb5759598
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For example, MR and CD163 proteins are upregulated in perivascular microglia, suggesting alternative activation (Galea et al. >>2005<<).
n3:mentions
n4:15538754
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_:vb5759599
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Herber et al. (>>2007<<) have recently shown that injection of LPS into brains of APP Tg2576 mice resulted in clearance of Aβ from the brain.
n3:mentions
n4:18040847
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_:vb5759600
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While demonstrating neuroinflammatory profiles reminiscent of humans with AD, mouse models of AD show minimal neuronal loss even when levels of toxic Aβ species are high (Lesne et al. >>2006<<; Jimenez et al. 2008; Radde et al. 2008).
n3:mentions
n4:16541076
Subject Item
_:vb5759601
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n3:Context
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While demonstrating neuroinflammatory profiles reminiscent of humans with AD, mouse models of AD show minimal neuronal loss even when levels of toxic Aβ species are high (Lesne et al. 2006; Jimenez et al. >>2008<<; Radde et al. 2008).
n3:mentions
n4:18987201
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_:vb5759602
rdf:type
n3:Context
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While demonstrating neuroinflammatory profiles reminiscent of humans with AD, mouse models of AD show minimal neuronal loss even when levels of toxic Aβ species are high (Lesne et al. 2006; Jimenez et al. 2008; Radde et al. >>2008<<). This puzzling observation suggests that immune-mediated damage in amyloid-mediated chronic neuroinflammation in mice is different from humans with AD where neuronal damage is prominent and/or that factors other than inflammation
n3:mentions
n4:18270700
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_:vb5759603
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n3:Context
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hyperphosphorylated and aggregated normal mouse tau in the somatodendritic neuronal compartment, (3) neurodegeneration and significant neuronal loss, including loss of interneurons, and (4) robust cognitive deficits (Colton et al. 2006b; Wilcock et al. 2008). These pathologies are not seen in NOS2−/− or APP alone, rather, it is the combination of both that creates the AD-like pathological changes.
n3:mentions
n4:16908860
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_:vb5759604
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n3:Context
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and aggregated normal mouse tau in the somatodendritic neuronal compartment, (3) neurodegeneration and significant neuronal loss, including loss of interneurons, and (4) robust cognitive deficits (Colton et al. 2006b; Wilcock et al. >>2008<<). These pathologies are not seen in NOS2−/− or APP alone, rather, it is the combination of both that creates the AD-like pathological changes.
n3:mentions
n4:18272675
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_:vb5759605
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n3:Context
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Significant differences in the gene promoter in human NOS2 compared to mouse NOS2 result in the production of different NO levels by human microglia or peripheral macrophages compared to rodents (Colton et al. >>1996<<; Ganster et al. 2001; Mestas and Hughes 2004; Snell et al. 1997; Weinberg et al. 1995).
n3:mentions
n4:8871937
Subject Item
_:vb5759606
rdf:type
n3:Context
rdf:value
Significant differences in the gene promoter in human NOS2 compared to mouse NOS2 result in the production of different NO levels by human microglia or peripheral macrophages compared to rodents (Colton et al. 1996; Ganster et al. >>2001<<; Mestas and Hughes 2004; Snell et al. 1997; Weinberg et al. 1995).
n3:mentions
n4:11438703
Subject Item
_:vb5759607
rdf:type
n3:Context
rdf:value
in the gene promoter in human NOS2 compared to mouse NOS2 result in the production of different NO levels by human microglia or peripheral macrophages compared to rodents (Colton et al. 1996; Ganster et al. 2001; Mestas and Hughes >>2004<<; Snell et al. 1997; Weinberg et al. 1995).
n3:mentions
n4:14978070
Subject Item
_:vb5759608
rdf:type
n3:Context
rdf:value
in human NOS2 compared to mouse NOS2 result in the production of different NO levels by human microglia or peripheral macrophages compared to rodents (Colton et al. 1996; Ganster et al. 2001; Mestas and Hughes 2004; Snell et al. >>1997<<; Weinberg et al. 1995).
n3:mentions
n4:9307076
Subject Item
_:vb5759609
rdf:type
n3:Context
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to mouse NOS2 result in the production of different NO levels by human microglia or peripheral macrophages compared to rodents (Colton et al. 1996; Ganster et al. 2001; Mestas and Hughes 2004; Snell et al. 1997; Weinberg et al. >>1995<<).
n3:mentions
n4:7542498
Subject Item
_:vb5759610
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One of the primary functions of NO in any tissue is to serve as an antioxidant (Ridnour et al. >>2004<<; Wink et al. 1993, 2001).
n3:mentions
n4:14977040
Subject Item
_:vb5759611
rdf:type
n3:Context
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One of the primary functions of NO in any tissue is to serve as an antioxidant (Ridnour et al. 2004; Wink et al. >>1993<<, 2001). Reduction in the integrated tissue levels of NO by lack of NO production, by increased scavenging of NO, or by chemical interactions of NO with cellular constituents promotes prooxidative conditions. Thomas et al. (2008) have
n3:mentions
n4:8234317
Subject Item
_:vb5759612
rdf:type
n3:Context
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One of the primary functions of NO in any tissue is to serve as an antioxidant (Ridnour et al. 2004; Wink et al. 1993, >>2001<<). Reduction in the integrated tissue levels of NO by lack of NO production, by increased scavenging of NO, or by chemical interactions of NO with cellular constituents promotes prooxidative conditions. Thomas et al. (2008) have provided
n3:mentions
n4:11396476
Subject Item
_:vb5759613
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Thomas et al. (>>2008<<) have provided an elegant study using cultured cells that clearly demonstrates this concept.
n3:mentions
n4:18439435
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_:vb5759614
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Our laboratory and others showed a number of years ago that Aβ treatment of microglia increased superoxide anion production (Colton et al. >>2000<<; Van Muiswinkel et al. 1996).
n3:mentions
n4:10863548
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_:vb5759615
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Our laboratory and others showed a number of years ago that Aβ treatment of microglia increased superoxide anion production (Colton et al. 2000; Van Muiswinkel et al. >>1996<<). Recently, Wilkinson et al. (2006) have shown that Aβ interaction with microglial membranes is mediated by CD36, CD47, and α6β1 integrin. Formation of the cross-linked receptor complex on the membrane initiates a signaling pathway
n3:mentions
n4:8632171
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_:vb5759616
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Recently, Wilkinson et al. (>>2006<<) have shown that Aβ interaction with microglial membranes is mediated by CD36, CD47, and α6β1 integrin.
n3:mentions
n4:16728400
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_:vb5759617
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Furthermore, Shimohama et al. (>>2000<<) have shown that NADPH oxidase expression is upregulated in AD brain.
n3:mentions
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42
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37
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30
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28
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28
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27
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27
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27
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25
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25
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25
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23
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22
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22
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21
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21
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19
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18
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17
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17
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17
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16
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16
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16
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16
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15
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15
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15
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14
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14
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13
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13
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13
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12
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12
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12
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11
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11
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11
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11
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11
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11
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11
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10
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10
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10
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10
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10
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10
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10
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10
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10
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10
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