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n3:pmcid
PMC0
bibo:doi
10.1002%2Fglia.22375
n2:contains
_:vb16714644 _:vb16714604 _:vb16714617 _:vb16714563
Subject Item
_:vb16714563
rdf:type
n2:Section
dc:title
introduction
n2:contains
_:vb16714600 _:vb16714601 _:vb16714602 _:vb16714603 _:vb16714592 _:vb16714593 _:vb16714594 _:vb16714595 _:vb16714596 _:vb16714597 _:vb16714598 _:vb16714599 _:vb16714568 _:vb16714569 _:vb16714570 _:vb16714571 _:vb16714572 _:vb16714573 _:vb16714574 _:vb16714575 _:vb16714564 _:vb16714565 _:vb16714566 _:vb16714567 _:vb16714584 _:vb16714585 _:vb16714586 _:vb16714587 _:vb16714588 _:vb16714589 _:vb16714590 _:vb16714591 _:vb16714576 _:vb16714577 _:vb16714578 _:vb16714579 _:vb16714580 _:vb16714581 _:vb16714582 _:vb16714583
Subject Item
_:vb16714564
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n3:Context
rdf:value
In addition to inducing an antiviral state, IFNα/β exert numerous other functions including induction of apoptosis, mobilizing innate cells, and regulating adaptive immune responses (Barton,>>2008<<; Borden et al.
n3:mentions
n4:18246191
Subject Item
_:vb16714565
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n3:Context
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immune responses. In addition to inducing an antiviral state, IFNα/β exert numerous other functions including induction of apoptosis, mobilizing innate cells, and regulating adaptive immune responses (Barton,2008; Borden et al.,>>2007<<; Stetson and Medzhitov,2006; Vilcek,2006). As these pleiotropic effects can be detrimental if left unregulated, the innate antiviral response has to be controlled to minimize cell injury and maintain cellular homeostatic functions.
n3:mentions
n4:18049472
Subject Item
_:vb16714566
rdf:type
n3:Context
rdf:value
,2007; Stetson and Medzhitov,>>2006<<; Vilcek,2006). As these pleiotropic effects can be detrimental if left unregulated, the innate antiviral response has to be controlled to minimize cell injury and maintain cellular homeostatic functions.
n3:mentions
n4:16979569
Subject Item
_:vb16714567
rdf:type
n3:Context
rdf:value
,2007; Stetson and Medzhitov,2006; Vilcek,>>2006<<). As these pleiotropic effects can be detrimental if left unregulated, the innate antiviral response has to be controlled to minimize cell injury and maintain cellular homeostatic functions.
n3:mentions
n4:16979566
Subject Item
_:vb16714568
rdf:type
n3:Context
rdf:value
PRRs comprise members of the Toll‐like receptor (TLR) family and the cytosolic helicase sensors, retinoic acid‐inducible gene 1 (RIG‐I), and melanoma differentiation‐associated antigen 5 (MDA5) (Kawai and Akira,>>2009<<; Mogensen,2009).
n3:mentions
n4:19246554
Subject Item
_:vb16714569
rdf:type
n3:Context
rdf:value
PRRs comprise members of the Toll‐like receptor (TLR) family and the cytosolic helicase sensors, retinoic acid‐inducible gene 1 (RIG‐I), and melanoma differentiation‐associated antigen 5 (MDA5) (Kawai and Akira,2009; Mogensen,>>2009<<). PRR recognition of viral RNA triggers the activation and nuclear localization of interferon regulatory factors (IRF) IRF3 and IRF7 leading to IFNα/β induction.
n3:mentions
n4:19366914
Subject Item
_:vb16714570
rdf:type
n3:Context
rdf:value
a signaling cascade leading to transcription of a variety of interferon stimulated genes (ISG). ISG encode both direct antiviral factors as well as PRR and signal transduction components, such as IRF7 and STAT1 (Borden et al.,>>2007<<). This amplification loop thus elevates the ability of cells to induce and respond to IFNα/β.
n3:mentions
n4:18049472
Subject Item
_:vb16714571
rdf:type
n3:Context
rdf:value
In general IRF7 is considered the master switch in IFNα/β induction following various viral infections due to its role in amplifying IFNα/β production (Honda and Taniguchi,>>2006<<). Because the pattern as well as levels of PRR, IRF, and IFNα/β receptor expression and activation varies with each cell type, initial IFNα/β induction and amplification can be very distinct depending on the cell types infected
n3:mentions
n4:16932750
Subject Item
_:vb16714572
rdf:type
n3:Context
rdf:value
Because the pattern as well as levels of PRR, IRF, and IFNα/β receptor expression and activation varies with each cell type, initial IFNα/β induction and amplification can be very distinct depending on the cell types infected (Colonna,>>2007<<; Stewart et al.,2005).
n3:mentions
n4:17273997
Subject Item
_:vb16714573
rdf:type
n3:Context
rdf:value
well as levels of PRR, IRF, and IFNα/β receptor expression and activation varies with each cell type, initial IFNα/β induction and amplification can be very distinct depending on the cell types infected (Colonna,2007; Stewart et al.,>>2005<<). Furthermore, due to the potency of IFNα/β in inhibiting viral replication, many viruses have evolved mechanisms to antagonize the IFNα/β pathway, either at the induction or signaling level (Levy and Garcia‐Sastre,2001; Sen,2001).
n3:mentions
n4:15709018
Subject Item
_:vb16714574
rdf:type
n3:Context
rdf:value
Furthermore, due to the potency of IFNα/β in inhibiting viral replication, many viruses have evolved mechanisms to antagonize the IFNα/β pathway, either at the induction or signaling level (Levy and Garcia‐Sastre,>>2001<<; Sen,2001).
n3:mentions
n4:11325598
Subject Item
_:vb16714575
rdf:type
n3:Context
rdf:value
Furthermore, due to the potency of IFNα/β in inhibiting viral replication, many viruses have evolved mechanisms to antagonize the IFNα/β pathway, either at the induction or signaling level (Levy and Garcia‐Sastre,2001; Sen,>>2001<<). Microglia and astrocytes are primary sentinels within the CNS parenchyma responding to stimuli triggered by either microbial infection or degenerative events (Dong and Benveniste,2001; Hanisch,2002; Paul et al.,2007). This function is
n3:mentions
n4:11544356
Subject Item
_:vb16714576
rdf:type
n3:Context
rdf:value
Microglia and astrocytes are primary sentinels within the CNS parenchyma responding to stimuli triggered by either microbial infection or degenerative events (Dong and Benveniste,>>2001<<; Hanisch,2002; Paul et al.
n3:mentions
n4:11596126
Subject Item
_:vb16714577
rdf:type
n3:Context
rdf:value
Microglia and astrocytes are primary sentinels within the CNS parenchyma responding to stimuli triggered by either microbial infection or degenerative events (Dong and Benveniste,2001; Hanisch,>>2002<<; Paul et al.
n3:mentions
n4:12379902
Subject Item
_:vb16714578
rdf:type
n3:Context
rdf:value
Sen,2001). Microglia and astrocytes are primary sentinels within the CNS parenchyma responding to stimuli triggered by either microbial infection or degenerative events (Dong and Benveniste,2001; Hanisch,2002; Paul et al.,>>2007<<). This function is partially attributed to basal expression of a vast array of PRRs (Bsibsi et al.
n3:mentions
n4:17408841
Subject Item
_:vb16714579
rdf:type
n3:Context
rdf:value
to stimuli triggered by either microbial infection or degenerative events (Dong and Benveniste,2001; Hanisch,2002; Paul et al.,2007). This function is partially attributed to basal expression of a vast array of PRRs (Bsibsi et al.,>>2002<<; Carty and Bowie,2011; Hanke and Kielian,2011; Okun et al.,2009; van Noort and Bsibsi,2009).
n3:mentions
n4:12430718
Subject Item
_:vb16714580
rdf:type
n3:Context
rdf:value
,2002; Carty and Bowie,>>2011<<; Hanke and Kielian,2011; Okun et al.,2009; van Noort and Bsibsi,2009).
n3:mentions
n4:21241665
Subject Item
_:vb16714581
rdf:type
n3:Context
rdf:value
,2002; Carty and Bowie,2011; Hanke and Kielian,>>2011<<; Okun et al.,2009; van Noort and Bsibsi,2009).
n3:mentions
n4:21745188
Subject Item
_:vb16714582
rdf:type
n3:Context
rdf:value
events (Dong and Benveniste,2001; Hanisch,2002; Paul et al.,2007). This function is partially attributed to basal expression of a vast array of PRRs (Bsibsi et al.,2002; Carty and Bowie,2011; Hanke and Kielian,2011; Okun et al.,>>2009<<; van Noort and Bsibsi,2009). Irf3 mRNA, and to a lesser extent Irf7 mRNA, are constitutively expressed in the CNS.
n3:mentions
n4:18822314
Subject Item
_:vb16714583
rdf:type
n3:Context
rdf:value
,2009; van Noort and Bsibsi,>>2009<<). Irf3 mRNA, and to a lesser extent Irf7 mRNA, are constitutively expressed in the CNS.
n3:mentions
n4:19660653
Subject Item
_:vb16714584
rdf:type
n3:Context
rdf:value
al.,2009; van Noort and Bsibsi,2009). Irf3 mRNA, and to a lesser extent Irf7 mRNA, are constitutively expressed in the CNS. While Irf7 expression is highly inducible, Irf3 transcripts remain constant following infection (Ousman et al.,>>2005<<). However, their relative expression in different cell types has not been extensively explored.
n3:mentions
n4:15919906
Subject Item
_:vb16714585
rdf:type
n3:Context
rdf:value
following infection (Ousman et al.,2005). However, their relative expression in different cell types has not been extensively explored. Consistent with PRR activation, microglia, astrocytes, and neurons all induce IFNα/β (Paul et al.,>>2007<<). However, the vast majority of information on CNS innate responsiveness is derived from primary glia and neuronal cultures established from neonates and may not reflect responsiveness of fully differentiated cells.
n3:mentions
n4:17408841
Subject Item
_:vb16714586
rdf:type
n3:Context
rdf:value
in vitro studies, IFNα/β production in vivo is highly restricted as indicated by the small proportion (<5%) of infected neurons with detectable IFNα/β expression in mice infected with lymphocytic choriomeningitis virus (Delhaye et al.,>>2006<<). Furthermore, IFNα/β inducible Irf7 transcripts mapped closely to sites of viral RNA (Ousman et al.
n3:mentions
n4:16682623
Subject Item
_:vb16714587
rdf:type
n3:Context
rdf:value
of infected neurons with detectable IFNα/β expression in mice infected with lymphocytic choriomeningitis virus (Delhaye et al.,2006). Furthermore, IFNα/β inducible Irf7 transcripts mapped closely to sites of viral RNA (Ousman et al.,>>2005<<), supporting highly focal IFNα/β responses. Overall however, little is known about responsiveness of distinct CNS cell types to viral infections in vivo.
n3:mentions
n4:15919906
Subject Item
_:vb16714588
rdf:type
n3:Context
rdf:value
Specifically oligodendroglia appear to express a limited TLR repertoire at basal levels compared with microglia (Hanke and Kielian,>>2011<<; Okun et al.
n3:mentions
n4:21745188
Subject Item
_:vb16714589
rdf:type
n3:Context
rdf:value
Specifically oligodendroglia appear to express a limited TLR repertoire at basal levels compared with microglia (Hanke and Kielian,2011; Okun et al.,>>2009<<; Paul et al.,2007).
n3:mentions
n4:18822314
Subject Item
_:vb16714590
rdf:type
n3:Context
rdf:value
of distinct CNS cell types to viral infections in vivo. Specifically oligodendroglia appear to express a limited TLR repertoire at basal levels compared with microglia (Hanke and Kielian,2011; Okun et al.,2009; Paul et al.,>>2007<<). They also do not appear to contribute to extensive proinflammatory cytokine secretion (Cannella and Raine,2004).
n3:mentions
n4:17408841
Subject Item
_:vb16714591
rdf:type
n3:Context
rdf:value
They also do not appear to contribute to extensive proinflammatory cytokine secretion (Cannella and Raine,>>2004<<).
n3:mentions
n4:14705111
Subject Item
_:vb16714592
rdf:type
n3:Context
rdf:value
strand RNA coronavirus family, was used to better characterize the ability of oligodendroglia to mount innate antiviral immune responses in vivo based on its prominent infection and persistence in oligodendroglia (Bergmann et al.,>>2006<<). In adult mice, JHMV infection causes an acute encephalomyelitis, which resolves into a persistent infection of the spinal cord associated with demyelination.
n3:mentions
n4:16415928
Subject Item
_:vb16714593
rdf:type
n3:Context
rdf:value
of the spinal cord associated with demyelination. In addition to oligodendroglia, JHMV also infects microglia and infiltrating macrophages during acute infection; however, neuronal and astrocyte infection is sparse (Ireland et al.,>>2008<<, 2009). Coronaviruses are poor inducers of IFNα/β in numerous cell types due to their 5′RNA structures mimicking self RNA (Daffis et al.
n3:mentions
n4:17928334
Subject Item
_:vb16714594
rdf:type
n3:Context
rdf:value
,2008, >>2009<<). Coronaviruses are poor inducers of IFNα/β in numerous cell types due to their 5′RNA structures mimicking self RNA (Daffis et al.
n3:mentions
n4:19798426
Subject Item
_:vb16714595
rdf:type
n3:Context
rdf:value
Coronaviruses are poor inducers of IFNα/β in numerous cell types due to their 5′RNA structures mimicking self RNA (Daffis et al.,>>2010<<; Zust et al.,2011).
n3:mentions
n4:21085181
Subject Item
_:vb16714596
rdf:type
n3:Context
rdf:value
however, neuronal and astrocyte infection is sparse (Ireland et al.,2008, 2009). Coronaviruses are poor inducers of IFNα/β in numerous cell types due to their 5′RNA structures mimicking self RNA (Daffis et al.,2010; Zust et al.,>>2011<<). However, IFNα/β is induced in microglia, macrophages, and plasmacytoid dendritic cells (Cervantes‐Barragan et al.
n3:mentions
n4:21217758
Subject Item
_:vb16714597
rdf:type
n3:Context
rdf:value
However, IFNα/β is induced in microglia, macrophages, and plasmacytoid dendritic cells (Cervantes‐Barragan et al.,>>2007<<; Roth‐Cross et al.,2008).
n3:mentions
n4:16985170
Subject Item
_:vb16714598
rdf:type
n3:Context
rdf:value
types due to their 5′RNA structures mimicking self RNA (Daffis et al.,2010; Zust et al.,2011). However, IFNα/β is induced in microglia, macrophages, and plasmacytoid dendritic cells (Cervantes‐Barragan et al.,2007; Roth‐Cross et al.,>>2008<<). Importantly, a protective effect of IFNα/β in vivo was highlighted by uncontrolled MHV replication in mice deficient in IFNα/β signaling (Cervantes‐Barragan et al.
n3:mentions
n4:18667505
Subject Item
_:vb16714599
rdf:type
n3:Context
rdf:value
Importantly, a protective effect of IFNα/β in vivo was highlighted by uncontrolled MHV replication in mice deficient in IFNα/β signaling (Cervantes‐Barragan et al.,>>2007<<; Ireland et al.,2008).
n3:mentions
n4:16985170
Subject Item
_:vb16714600
rdf:type
n3:Context
rdf:value
et al.,2007; Roth‐Cross et al.,2008). Importantly, a protective effect of IFNα/β in vivo was highlighted by uncontrolled MHV replication in mice deficient in IFNα/β signaling (Cervantes‐Barragan et al.,2007; Ireland et al.,>>2008<<). Furthermore, protection following peripheral MHV infection is associated with TLR7 dependent IFNα/β production by plasmacytoid dendritic cells (Cervantes‐Barragan et al.
n3:mentions
n4:17928334
Subject Item
_:vb16714601
rdf:type
n3:Context
rdf:value
Furthermore, protection following peripheral MHV infection is associated with TLR7 dependent IFNα/β production by plasmacytoid dendritic cells (Cervantes‐Barragan et al.,>>2007<<). The naïve CNS is devoid of plasmacytoid dendritic cells (Serafini et al.
n3:mentions
n4:16985170
Subject Item
_:vb16714602
rdf:type
n3:Context
rdf:value
following peripheral MHV infection is associated with TLR7 dependent IFNα/β production by plasmacytoid dendritic cells (Cervantes‐Barragan et al.,2007). The naïve CNS is devoid of plasmacytoid dendritic cells (Serafini et al.,>>2000<<), implicating infected glia as primary candidates contributing to protective IFNα/β production following CNS infection.
n3:mentions
n4:11106572
Subject Item
_:vb16714603
rdf:type
n3:Context
rdf:value
This is supported by MDA5 mediated IFNα/β production in infected microglia (Roth‐Cross et al.,>>2008<<).
n3:mentions
n4:18667505
Subject Item
_:vb16714604
rdf:type
n2:Section
dc:title
materials and methods
n2:contains
_:vb16714612 _:vb16714613 _:vb16714614 _:vb16714615 _:vb16714608 _:vb16714609 _:vb16714610 _:vb16714611 _:vb16714616 _:vb16714605 _:vb16714606 _:vb16714607
Subject Item
_:vb16714605
rdf:type
n3:Context
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C57BL/6 wild type (Wt) mice were purchased from the National Cancer Institute (Frederick, MD). Mice expressing green fluorescent protein (GFP) under the control of the proteolipid protein (PLP) promoter (PLP‐GFP) (Fuss et al.,>>2000<<) were backcrossed six times with C57BL/6 mice prior to use (Malone et al.,2008).
n3:mentions
n4:10656768
Subject Item
_:vb16714606
rdf:type
n3:Context
rdf:value
(Frederick, MD). Mice expressing green fluorescent protein (GFP) under the control of the proteolipid protein (PLP) promoter (PLP‐GFP) (Fuss et al.,2000) were backcrossed six times with C57BL/6 mice prior to use (Malone et al.,>>2008<<). Congenic mice defective in IFNα/β signaling (IFNAR−/−) were previously described (Ireland et al.
n3:mentions
n4:18205173
Subject Item
_:vb16714607
rdf:type
n3:Context
rdf:value
protein (PLP) promoter (PLP‐GFP) (Fuss et al.,2000) were backcrossed six times with C57BL/6 mice prior to use (Malone et al.,2008). Congenic mice defective in IFNα/β signaling (IFNAR−/−) were previously described (Ireland et al.,>>2008<<). Mice at 6–7 weeks of age were infected via intracerebral injection with 250 Plaque Forming Units of the neutralizing monoclonal antibody (mAb)‐derived JHMV variant, designated V2.2v‐1 (Fleming et al.
n3:mentions
n4:17928334
Subject Item
_:vb16714608
rdf:type
n3:Context
rdf:value
described (Ireland et al.,2008). Mice at 6–7 weeks of age were infected via intracerebral injection with 250 Plaque Forming Units of the neutralizing monoclonal antibody (mAb)‐derived JHMV variant, designated V2.2v‐1 (Fleming et al.,>>1986<<) in 30 μL of endotoxin‐free Dulbecco's modified phosphate‐buffered saline (PBS).
n3:mentions
n4:3701929
Subject Item
_:vb16714609
rdf:type
n3:Context
rdf:value
Mononuclear cells were isolated from spinal cords as described previously (Malone et al.,>>2008<<; Phares et al.,2009). Briefly, spinal cords from six to seven mice were finely minced, digested in PBS containing 0.25% trypsin for 30 min at 37°C, and trypsin quenched by addition of 20% new born calf serum.
n3:mentions
n4:18205173
Subject Item
_:vb16714610
rdf:type
n3:Context
rdf:value
Mononuclear cells were isolated from spinal cords as described previously (Malone et al.,2008; Phares et al.,>>2009<<). Briefly, spinal cords from six to seven mice were finely minced, digested in PBS containing 0.25% trypsin for 30 min at 37°C, and trypsin quenched by addition of 20% new born calf serum.
n3:mentions
n4:19380790
Subject Item
_:vb16714611
rdf:type
n3:Context
rdf:value
PLP‐GFP transgenic mice facilitated identification of oligodendroglia via their CD45− GFP+ phenotype (Malone et al.,>>2008<<). Oligodendroglia from IFNAR−/− and Wt control mice were identified by consecutive staining with unconjugated O4 mAb and anti‐mouse IgM (PE) mAb (R6‐60.2) (BD Pharmingen) and purified based on their CD45− O4+ phenotype as described
n3:mentions
n4:18205173
Subject Item
_:vb16714612
rdf:type
n3:Context
rdf:value
from IFNAR−/− and Wt control mice were identified by consecutive staining with unconjugated O4 mAb and anti‐mouse IgM (PE) mAb (R6‐60.2) (BD Pharmingen) and purified based on their CD45− O4+ phenotype as described (Gonzalez et al.,>>2005<<; Phares et al.,2011). Cells were purified on a BD FACSAria (BD Biosciences), resuspended in TRIzol (Invitrogen, Carlsbad, CA) and stored at −80°C.
n3:mentions
n4:15779088
Subject Item
_:vb16714613
rdf:type
n3:Context
rdf:value
Wt control mice were identified by consecutive staining with unconjugated O4 mAb and anti‐mouse IgM (PE) mAb (R6‐60.2) (BD Pharmingen) and purified based on their CD45− O4+ phenotype as described (Gonzalez et al.,2005; Phares et al.,>>2011<<). Cells were purified on a BD FACSAria (BD Biosciences), resuspended in TRIzol (Invitrogen, Carlsbad, CA) and stored at −80°C.
n3:mentions
n4:21191015
Subject Item
_:vb16714614
rdf:type
n3:Context
rdf:value
RNA was extracted by dissociation in TRIzol reagent (Invitrogen) according to the manufacturer's instructions and subjected to real‐time PCR analysis as described (Phares et al.,>>2011<<). In brief, snap‐frozen spinal cords or FACS‐purified cells were homogenized with TRIzol in a Tissuelyser II (Qiagen, Valencia, CA) or by pipetting, respectively, and treated with chloroform.
n3:mentions
n4:21191015
Subject Item
_:vb16714615
rdf:type
n3:Context
rdf:value
dehydrogenase (GAPDH) using the following formula: 2[CT(GAPDH) – CT(Target Gene)] × 1,000, where CT represents the threshold cycle at which the fluorescent signal becomes higher than the background (Kapil et al.,>>2009<<; Phares et al.,2009).
n3:mentions
n4:19339350
Subject Item
_:vb16714616
rdf:type
n3:Context
rdf:value
,2009; Phares et al.,>>2009<<).
n3:mentions
n4:19380790
Subject Item
_:vb16714617
rdf:type
n2:Section
dc:title
results
n2:contains
_:vb16714618 _:vb16714619 _:vb16714620 _:vb16714621 _:vb16714622 _:vb16714623 _:vb16714624 _:vb16714625 _:vb16714626 _:vb16714627 _:vb16714628 _:vb16714629 _:vb16714630 _:vb16714631 _:vb16714632 _:vb16714633 _:vb16714634 _:vb16714635 _:vb16714636 _:vb16714637 _:vb16714638 _:vb16714639 _:vb16714640 _:vb16714641 _:vb16714642 _:vb16714643
Subject Item
_:vb16714618
rdf:type
n3:Context
rdf:value
Induction of IFNα/β by murine coronaviruses is mediated via TLR7 in pDC and via MDA5 in microglia/monocytes (Cervantes‐Barragan et al.,>>2007<<; Roth‐Cross et al.,2008). Furthermore, both MDA5 and RIG‐1 act as PRR in an oligodendroglia cell line (Li et al.
n3:mentions
n4:16985170
Subject Item
_:vb16714619
rdf:type
n3:Context
rdf:value
Induction of IFNα/β by murine coronaviruses is mediated via TLR7 in pDC and via MDA5 in microglia/monocytes (Cervantes‐Barragan et al.,2007; Roth‐Cross et al.,>>2008<<). Furthermore, both MDA5 and RIG‐1 act as PRR in an oligodendroglia cell line (Li et al.
n3:mentions
n4:18667505
Subject Item
_:vb16714620
rdf:type
n3:Context
rdf:value
by murine coronaviruses is mediated via TLR7 in pDC and via MDA5 in microglia/monocytes (Cervantes‐Barragan et al.,2007; Roth‐Cross et al.,2008). Furthermore, both MDA5 and RIG‐1 act as PRR in an oligodendroglia cell line (Li et al.,>>2010<<). However, the expression of these viral sensors in oligodendroglia in the adult CNS is unknown.
n3:mentions
n4:20427526
Subject Item
_:vb16714621
rdf:type
n3:Context
rdf:value
analyze their capacity to initiate innate responses, oligodendroglia and microglia were isolated from spinal cords of uninfected PLP‐GFP mice by FACS based on their respective CD45− GFP+ and CD45lo/int F4/80+ phenotypes (Malone et al.,>>2008<<). Spinal cords were used as donor tissue based on higher oligodendroglia yields compared with brains.
n3:mentions
n4:18205173
Subject Item
_:vb16714622
rdf:type
n3:Context
rdf:value
The potential of mature oligodendroglia to recognize viral RNA in comparison to microglia was assessed by comparing basal transcript levels of genes encoding the viral RNA sensors MDA5, RIG‐I, TLR3, and TLR7 (Kawai and Akira,>>2007<<). Whereas transcription of all four PRR was readily detected in microglia, Mda5, Rig‐I, and Tlr3 transcripts were significantly reduced and Tlr7 was below detection in oligodendroglia (Fig. 1A). Basal levels of PRR mRNAs are low in the
n3:mentions
n4:17190786
Subject Item
_:vb16714623
rdf:type
n3:Context
rdf:value
and Tlr3 transcripts were significantly reduced and Tlr7 was below detection in oligodendroglia (Fig. 1A). Basal levels of PRR mRNAs are low in the resting CNS relative to lymphoid tissue, with the exception of Tlr3 (McKimmie et al.,>>2005<<). Nevertheless, PRR are rapidly upregulated during viral encephalitis initiated by Semliki Forest virus, Rabies virus, and Venezuelan Equine Encephalitis virus (McKimmie et al.
n3:mentions
n4:16157304
Subject Item
_:vb16714624
rdf:type
n3:Context
rdf:value
tissue, with the exception of Tlr3 (McKimmie et al.,2005). Nevertheless, PRR are rapidly upregulated during viral encephalitis initiated by Semliki Forest virus, Rabies virus, and Venezuelan Equine Encephalitis virus (McKimmie et al.,>>2005<<; Sharma and Maheshwari,2009). However, the relative contribution of infiltrating leukocytes versus resident CNS cells was not directly assessed.
n3:mentions
n4:16157304
Subject Item
_:vb16714625
rdf:type
n3:Context
rdf:value
,2005; Sharma and Maheshwari,>>2009<<). However, the relative contribution of infiltrating leukocytes versus resident CNS cells was not directly assessed.
n3:mentions
n4:19369408
Subject Item
_:vb16714626
rdf:type
n3:Context
rdf:value
Induction of Mda5 and Rig‐I in oligodendroglia, as well as all RNA sensing PRR in microglia, correlated with induction of Ifnα4 and Ifnβ mRNA in the CNS following JHMV infection (Ireland et al.,>>2008<<; Malone et al.,2008).
n3:mentions
n4:17928334
Subject Item
_:vb16714627
rdf:type
n3:Context
rdf:value
to microglia. Induction of Mda5 and Rig‐I in oligodendroglia, as well as all RNA sensing PRR in microglia, correlated with induction of Ifnα4 and Ifnβ mRNA in the CNS following JHMV infection (Ireland et al.,2008; Malone et al.,>>2008<<). To evaluate additional contributions of Type II (IFNγ) and Type III (IFNλ) IFN, which also induce ISG, the RNA expression kinetics of all three IFN families were assessed in spinal cords (Fig.
n3:mentions
n4:18205173
Subject Item
_:vb16714628
rdf:type
n3:Context
rdf:value
Confirming previous results (Malone et al.,>>2008<<) Ifnα4 and Ifnβ mRNA were increased at Day 3 and peaked at Day 5 p.i.
n3:mentions
n4:18205173
Subject Item
_:vb16714629
rdf:type
n3:Context
rdf:value
IFNλ was minimally induced, yet with similar kinetics as IFNα/β, confirming very low expression and function in the CNS following heterologous infections, including a closely related MHV strain (Sommereyns et al.,>>2008<<). IFNγ mRNA was not upregulated until Day 5 p.
n3:mentions
n4:18369468
Subject Item
_:vb16714630
rdf:type
n3:Context
rdf:value
IFNAR−/− relative to Wt mice, they were only slightly reduced in oligodendroglia (Fig. 3). These results are reminiscent of previous observations that PRR expression in neurons is controlled by basal IFNα/β signaling (Shrestha et al.,>>2003<<). Importantly, the absence of IFNα/β signaling abrogated upregulation of Mda5 and Rig‐I transcripts in both microglia and oligodendroglia following JHMV infection (Fig.
n3:mentions
n4:14645577
Subject Item
_:vb16714631
rdf:type
n3:Context
rdf:value
IFNα/β signaling is crucial to prevent dissemination of gliatropic coronavirus within the CNS parenchyma (Ireland et al.,>>2008<<). Furthermore, IFNα/β induction in response to coronavirus infection has been demonstrated in microglia in vitro and in vivo (Roth‐Cross et al.
n3:mentions
n4:17928334
Subject Item
_:vb16714632
rdf:type
n3:Context
rdf:value
Furthermore, IFNα/β induction in response to coronavirus infection has been demonstrated in microglia in vitro and in vivo (Roth‐Cross et al.,>>2008<<) as well as in an oligodendroglial cell line (Li et al.,2010).
n3:mentions
n4:18667505
Subject Item
_:vb16714633
rdf:type
n3:Context
rdf:value
Furthermore, IFNα/β induction in response to coronavirus infection has been demonstrated in microglia in vitro and in vivo (Roth‐Cross et al.,2008) as well as in an oligodendroglial cell line (Li et al.,>>2010<<). Given the distinct basal and inducible levels of Mda5 transcripts in mature CNS derived glial populations, the contribution of infected oligodendroglia and microglia to IFNα/β induction was assessed in vivo by comparing Ifnβ and Ifnα4
n3:mentions
n4:20427526
Subject Item
_:vb16714634
rdf:type
n3:Context
rdf:value
Viral loads were monitored by measuring viral mRNA encoding the N protein, the most abundant viral RNA in infected cells (Skinner and Siddell,>>1983<<). Viral‐N transcripts prevailed in microglia at Day 3 p.i., but decreased by Days 5 and 7 p.i. (Fig. 4). By contrast, although viral mRNA was near detection levels at Day 3 p.i. in oligodendroglia, the levels increased ∼20 fold relative
n3:mentions
n4:6308569
Subject Item
_:vb16714635
rdf:type
n3:Context
rdf:value
The contribution of infiltrating infected monocyte‐derived macrophages (Ireland et al.,>>2009<<) to Ifnα/β induction was also assessed.
n3:mentions
n4:19798426
Subject Item
_:vb16714636
rdf:type
n3:Context
rdf:value
While IRF3 is constitutively expressed, IRF7 is induced by IFNα/β and amplifies IFNα/β production (Honda and Taniguchi,>>2006<<; Honda et al.
n3:mentions
n4:16932750
Subject Item
_:vb16714637
rdf:type
n3:Context
rdf:value
inducible kinase IKKε (also known as Ikbke or Ikki) and the transcription factors IRF3 and IRF7. While IRF3 is constitutively expressed, IRF7 is induced by IFNα/β and amplifies IFNα/β production (Honda and Taniguchi,2006; Honda et al.,>>2005<<). Therefore to investigate the potential for PRR signaling, oligodendroglia were examined for expression of mRNAs encoding IKKε, IRF3, and IRF7.
n3:mentions
n4:15800576
Subject Item
_:vb16714638
rdf:type
n3:Context
rdf:value
tended to decline following infection (Fig. 5). Lastly, Irf7 transcripts were sparse in both microglia and oligodendroglia derived from naive mice (Fig. 5), consistent with lower basal CNS expression relative to Irf3 (Ousman et al.,>>2005<<). However, in contrast to the increase of Irf7 mRNA detected in microglia by Day 3 p.
n3:mentions
n4:15919906
Subject Item
_:vb16714639
rdf:type
n3:Context
rdf:value
IFNα/β binds a common receptor complex consisting of two transmembrane proteins, IFNAR1 and IFNAR2. As IFNAR2 exists as a soluble (IFNAR2a) and transmembrane (IFNAR2c) and isoform generated by alternative splicing (Domanski et al.,>>1995<<), we examined basal expression patterns of IFNAR1, and both IFNAR2 isoforms in microglia and oligodendroglia.
n3:mentions
n4:7665574
Subject Item
_:vb16714640
rdf:type
n3:Context
rdf:value
Irf9 levels were also elevated in microglia compared with oligodendroglia derived from naïve mice (Fig. 6B). STAT1 is inducible by both IFNα/β and IFNγ, while IRF9 is constitutively expressed in most non CNS cell types (Borden et al.,>>2007<<). Consistent with a response to IFNα/β, Stat1 mRNA indeed increased ∼10 fold by Day 3 p.
n3:mentions
n4:18049472
Subject Item
_:vb16714641
rdf:type
n3:Context
rdf:value
Transcripts encoding adenosine deaminase specific for mRNA (Adar1), which limits viral replication via introduction of mRNA mutations (Bass,>>1997<<), were also more abundant in microglia (Fig.
n3:mentions
n4:9175473
Subject Item
_:vb16714642
rdf:type
n3:Context
rdf:value
Poly I:C is a strong agonist of both TLR3 and the RIG‐like receptors RIG‐I/MDA5 (Alexopoulou et al.,>>2001<<; Kato et al.,2006).
n3:mentions
n4:11607032
Subject Item
_:vb16714643
rdf:type
n3:Context
rdf:value
JHMV infection, we assessed IFNα/β and ISG induction following intracerebral injection of the PRR ligand poly I:C. Poly I:C is a strong agonist of both TLR3 and the RIG‐like receptors RIG‐I/MDA5 (Alexopoulou et al.,2001; Kato et al.,>>2006<<). Ifnα/β upregulation was initially tested in total tissue to characterize the time course of poly I:
n3:mentions
n4:16625202
Subject Item
_:vb16714644
rdf:type
n2:Section
dc:title
discussion
n2:contains
_:vb16714650 _:vb16714651 _:vb16714676 _:vb16714677 _:vb16714678 _:vb16714679 _:vb16714672 _:vb16714673 _:vb16714674 _:vb16714675 _:vb16714680 _:vb16714681 _:vb16714660 _:vb16714661 _:vb16714662 _:vb16714663 _:vb16714656 _:vb16714657 _:vb16714658 _:vb16714659 _:vb16714668 _:vb16714669 _:vb16714670 _:vb16714671 _:vb16714664 _:vb16714665 _:vb16714666 _:vb16714667 _:vb16714645 _:vb16714646 _:vb16714647 _:vb16714652 _:vb16714653 _:vb16714654 _:vb16714655 _:vb16714648 _:vb16714649
Subject Item
_:vb16714645
rdf:type
n3:Context
rdf:value
While PRR expression and activation in microglia and astrocytes has been extensively explored in vitro (Butchi et al.,>>2010<<; Carpentier et al.,2008; Jin et al.
n3:mentions
n4:19998480
Subject Item
_:vb16714646
rdf:type
n3:Context
rdf:value
are critical for the induction of IFNα/β, as well proinflammatory cytokines and chemokines. While PRR expression and activation in microglia and astrocytes has been extensively explored in vitro (Butchi et al.,2010; Carpentier et al.,>>2008<<; Jin et al.,2011; So and Kim,2009), expression of PRR and associated signaling components in glia in vivo are poorly defined, especially in oligodendroglia.
n3:mentions
n4:17920811
Subject Item
_:vb16714647
rdf:type
n3:Context
rdf:value
the induction of IFNα/β, as well proinflammatory cytokines and chemokines. While PRR expression and activation in microglia and astrocytes has been extensively explored in vitro (Butchi et al.,2010; Carpentier et al.,2008; Jin et al.,>>2011<<; So and Kim,2009), expression of PRR and associated signaling components in glia in vivo are poorly defined, especially in oligodendroglia.
n3:mentions
n4:22090123
Subject Item
_:vb16714648
rdf:type
n3:Context
rdf:value
,2011; So and Kim,>>2009<<), expression of PRR and associated signaling components in glia in vivo are poorly defined, especially in oligodendroglia.
n3:mentions
n4:19191335
Subject Item
_:vb16714649
rdf:type
n3:Context
rdf:value
Microglia were prominent inducers of Ifnα/β mRNA following infection, consistent with IFNα/β induction in primary microglia as well as bone marrow derived macrophages infected with a heterologous MHV (Roth‐Cross et al., >>2008<<). However, the inability of oligodendroglia to induce Ifnα/β mRNA, despite their high load of viral RNA, contrasted with in vitro studies demonstrating MDA5 and RIG‐I dependent IFNα/β induction in the infected N20.1 oligodendroglia cell
n3:mentions
n4:18667505
Subject Item
_:vb16714650
rdf:type
n3:Context
rdf:value
of oligodendroglia to induce Ifnα/β mRNA, despite their high load of viral RNA, contrasted with in vitro studies demonstrating MDA5 and RIG‐I dependent IFNα/β induction in the infected N20.1 oligodendroglia cell line (Li et al.,>>2010<<). This discrepancy likely reflects differences in expression and/or induction of IFNα/β pathway components, rather than distinct viral loads, as even poly I:
n3:mentions
n4:20427526
Subject Item
_:vb16714651
rdf:type
n3:Context
rdf:value
The restricted ability of coronaviruses to induce IFNα/β was recently attributed to the O‐methylated cap structure of the viral RNA, making it difficult for the host to distinguish viral from self mRNA (Daffis et al.,>>2010<<; Zust et al.,2011).
n3:mentions
n4:21085181
Subject Item
_:vb16714652
rdf:type
n3:Context
rdf:value
,2010; Zust et al.,>>2011<<). However, in contrast to cultured fibroblasts, bone marrow‐derived dendritic cells, astrocytes, and neurons, the ability of plasmacytoid dendritic cells, macrophages/microglia, and an oligodendroglia cell line to induce IFNα/β via TLR7,
n3:mentions
n4:21217758
Subject Item
_:vb16714653
rdf:type
n3:Context
rdf:value
cells, astrocytes, and neurons, the ability of plasmacytoid dendritic cells, macrophages/microglia, and an oligodendroglia cell line to induce IFNα/β via TLR7, MDA5 and MDA5/RIG‐I dependent pathways (Cervantes‐Barragan et al.,>>2007<<; Li et al.,2010; Roth‐Cross et al.,2008; Zhou and Perlman,2007) suggests sufficient PRR activation by viral RNA structures to mediate protective responses in select cell types.
n3:mentions
n4:16985170
Subject Item
_:vb16714654
rdf:type
n3:Context
rdf:value
astrocytes, and neurons, the ability of plasmacytoid dendritic cells, macrophages/microglia, and an oligodendroglia cell line to induce IFNα/β via TLR7, MDA5 and MDA5/RIG‐I dependent pathways (Cervantes‐Barragan et al.,2007; Li et al.,>>2010<<; Roth‐Cross et al.,2008; Zhou and Perlman,2007) suggests sufficient PRR activation by viral RNA structures to mediate protective responses in select cell types.
n3:mentions
n4:20427526
Subject Item
_:vb16714655
rdf:type
n3:Context
rdf:value
the ability of plasmacytoid dendritic cells, macrophages/microglia, and an oligodendroglia cell line to induce IFNα/β via TLR7, MDA5 and MDA5/RIG‐I dependent pathways (Cervantes‐Barragan et al.,2007; Li et al.,2010; Roth‐Cross et al.,>>2008<<; Zhou and Perlman,2007) suggests sufficient PRR activation by viral RNA structures to mediate protective responses in select cell types.
n3:mentions
n4:18667505
Subject Item
_:vb16714656
rdf:type
n3:Context
rdf:value
,2008; Zhou and Perlman,>>2007<<) suggests sufficient PRR activation by viral RNA structures to mediate protective responses in select cell types.
n3:mentions
n4:17079305
Subject Item
_:vb16714657
rdf:type
n3:Context
rdf:value
Ikkε. However, basal Irf3 transcripts were only reduced by ∼50%, and Irf7 transcripts were barely detectable in either cell population, consistent with higher basal Irf3 than Irf7 levels observed in whole naïve brains (Ousman et al.,>>2005<<). Reduced basal PRR levels in oligodendroglia were reminiscent of sparsely expressed PRRs in primary neurons (Carpentier et al.
n3:mentions
n4:15919906
Subject Item
_:vb16714658
rdf:type
n3:Context
rdf:value
consistent with higher basal Irf3 than Irf7 levels observed in whole naïve brains (Ousman et al.,2005). Reduced basal PRR levels in oligodendroglia were reminiscent of sparsely expressed PRRs in primary neurons (Carpentier et al.,>>2008<<), and supported the superior initiation of Ifnα/β responses by microglia. This concept is consistent with the inability of primary cultured neurons and astrocytes to induce IFNα/β expression following MHV infection (Roth‐Cross et al.
n3:mentions
n4:17920811
Subject Item
_:vb16714659
rdf:type
n3:Context
rdf:value
and supported the superior initiation of Ifnα/β responses by microglia. This concept is consistent with the inability of primary cultured neurons and astrocytes to induce IFNα/β expression following MHV infection (Roth‐Cross et al.,>>2008<<). It remains to be confirmed whether other CNS infections involving oligodendroglia reveal a similarly muted pattern of IFNα/β induction and responsiveness.
n3:mentions
n4:18667505
Subject Item
_:vb16714660
rdf:type
n3:Context
rdf:value
responsiveness. However, most RNA viruses are neuronotropic, with only some variants of Theilers murine encephalomyelitis virus displaying tropism for oligodendroglia in mouse strains susceptible to persistent infection (Brahic et al.,>>2005<<). However, during the acute CNS infection, this virus primarily infects neurons and oligodendroglia and is only infected during the persistent stage, making direct comparisons difficult.
n3:mentions
n4:16153171
Subject Item
_:vb16714661
rdf:type
n3:Context
rdf:value
Optimal IFNα/β induction requires amplification through IFNAR to elevate PRRs and IRF7 (Honda and Taniguchi,>>2006<<; Honda et al.,2005; Malmgaard et al.,2002). However, in contrast to Ifnα/β induction, IFNAR signaling was intact in oligodendroglia.
n3:mentions
n4:16932750
Subject Item
_:vb16714662
rdf:type
n3:Context
rdf:value
Optimal IFNα/β induction requires amplification through IFNAR to elevate PRRs and IRF7 (Honda and Taniguchi,2006; Honda et al.,>>2005<<; Malmgaard et al.,2002). However, in contrast to Ifnα/β induction, IFNAR signaling was intact in oligodendroglia.
n3:mentions
n4:15800576
Subject Item
_:vb16714663
rdf:type
n3:Context
rdf:value
Optimal IFNα/β induction requires amplification through IFNAR to elevate PRRs and IRF7 (Honda and Taniguchi,2006; Honda et al.,2005; Malmgaard et al.,>>2002<<). However, in contrast to Ifnα/β induction, IFNAR signaling was intact in oligodendroglia.
n3:mentions
n4:11932417
Subject Item
_:vb16714664
rdf:type
n3:Context
rdf:value
those reached in microglia, as exemplified by Stat1 and Irf7 mRNA. Furthermore, peak expression for many genes did not correlate with maximal Ifnα/β mRNA levels, but rather with peak IFNγ mRNA and protein at Day 7 p.i. (Phares et al.,>>2011<<). The distinct pattern of ISG expression in oligodendroglia compared with microglia may further reside in low IKKε.
n3:mentions
n4:21191015
Subject Item
_:vb16714665
rdf:type
n3:Context
rdf:value
In addition to mediating PRR signaling, IKKε influences ISG induction through participation in JAK/STAT mediated IFNα/β signaling (Pham and Tenoever,>>2010<<; Tenoever et al.
n3:mentions
n4:21994600
Subject Item
_:vb16714666
rdf:type
n3:Context
rdf:value
compared with microglia may further reside in low IKKε. In addition to mediating PRR signaling, IKKε influences ISG induction through participation in JAK/STAT mediated IFNα/β signaling (Pham and Tenoever,2010; Tenoever et al.,>>2007<<). Although not as severe as the complete abrogation of ISG induction in STAT1−/− mice, IKKε−/− mice lack induction of ∼30% of ISGs, including Adar1 (Durbin et al.
n3:mentions
n4:17332413
Subject Item
_:vb16714667
rdf:type
n3:Context
rdf:value
Although not as severe as the complete abrogation of ISG induction in STAT1−/− mice, IKKε−/− mice lack induction of ∼30% of ISGs, including Adar1 (Durbin et al.,>>1996<<; Tenoever et al.,2007).
n3:mentions
n4:8608598
Subject Item
_:vb16714668
rdf:type
n3:Context
rdf:value
(Pham and Tenoever,2010; Tenoever et al.,2007). Although not as severe as the complete abrogation of ISG induction in STAT1−/− mice, IKKε−/− mice lack induction of ∼30% of ISGs, including Adar1 (Durbin et al.,1996; Tenoever et al.,>>2007<<). The biological consequences are demonstrated by impaired clearance of influenza virus infection by IKKε−/− mice, despite similar expression of IL2, IL6, IL12, IFNγ, and RANTES as well as induction of antiviral antibody (Tenoever et al.
n3:mentions
n4:17332413
Subject Item
_:vb16714669
rdf:type
n3:Context
rdf:value
biological consequences are demonstrated by impaired clearance of influenza virus infection by IKKε−/− mice, despite similar expression of IL2, IL6, IL12, IFNγ, and RANTES as well as induction of antiviral antibody (Tenoever et al.,>>2007<<). The paucity of Ikkε mRNA and modest, if any, increase of Irf7 mRNA in oligodendroglia, despite abundant viral and Mda5 mRNA upregulation, may partially explain the absence of Ifnα/β expression and more selective and delayed ISG
n3:mentions
n4:17332413
Subject Item
_:vb16714670
rdf:type
n3:Context
rdf:value
This concept is consistent with data indicating that microglia are a dominant source of IFNα/β within the CNS during JHMV induced encephalomyelitis (Roth‐Cross et al., >>2008<<). The biological relevance of suboptimal IFNα/β responses is clearly evident from differential viral control in both cell types. A direct response to infection by microglia is supported by the correlation between peak viral and Ifnα/β
n3:mentions
n4:18667505
Subject Item
_:vb16714671
rdf:type
n3:Context
rdf:value
logs between Days 3 and 5 p.i., coincident with no Ifnα/β and tentative induction of antiviral ISGs. These data indicate that oligodendroglia rely largely on T cell effector function, prominently IFNγ, for viral control (Parra et al.,>>2010<<). Oligodendroglia are indeed highly responsive to IFNγ as indicated by upregulation of Class I MHC molecules and associated antigen processing components during peak IFNγ, but not IFNα/β induction during JHMV infection (Malone et al.
n3:mentions
n4:20042510
Subject Item
_:vb16714672
rdf:type
n3:Context
rdf:value
Oligodendroglia are indeed highly responsive to IFNγ as indicated by upregulation of Class I MHC molecules and associated antigen processing components during peak IFNγ, but not IFNα/β induction during JHMV infection (Malone et al.,>>2008<<). Moreover, specific blockade of IFNγ receptor signaling on oligodendroglia prolongs JHMV infection in this cell type (Gonzalez et al.
n3:mentions
n4:18205173
Subject Item
_:vb16714673
rdf:type
n3:Context
rdf:value
Moreover, specific blockade of IFNγ receptor signaling on oligodendroglia prolongs JHMV infection in this cell type (Gonzalez et al.,>>2005<<, 2006; Parra et al.,2010).
n3:mentions
n4:15779088
Subject Item
_:vb16714674
rdf:type
n3:Context
rdf:value
Moreover, specific blockade of IFNγ receptor signaling on oligodendroglia prolongs JHMV infection in this cell type (Gonzalez et al.,2005, >>2006<<; Parra et al.,2010).
n3:mentions
n4:16507895
Subject Item
_:vb16714675
rdf:type
n3:Context
rdf:value
IFNγ, but not IFNα/β induction during JHMV infection (Malone et al.,2008). Moreover, specific blockade of IFNγ receptor signaling on oligodendroglia prolongs JHMV infection in this cell type (Gonzalez et al.,2005, 2006; Parra et al.,>>2010<<). Whether early events favoring robust infection of oligodendroglia prior to emergence of T cells, contribute to ultimate persistence of JHMV in oligodendroglia, remains to be elucidated.
n3:mentions
n4:20042510
Subject Item
_:vb16714676
rdf:type
n3:Context
rdf:value
demonstrate a limited role of oligodendroglia as both inducers of, and responders to, IFNα/β compared with microglia. Limited innate antiviral activity may predispose oligodendroglia to be potent responders to IFNγ (Gonzalez et al.,>>2005<<; Popko and Baerwald,1999). While there is no evidence supporting toxicity of IFNα/β (Akwa et al.
n3:mentions
n4:15779088
Subject Item
_:vb16714677
rdf:type
n3:Context
rdf:value
,2005; Popko and Baerwald,>>1999<<). While there is no evidence supporting toxicity of IFNα/β (Akwa et al.
n3:mentions
n4:9972883
Subject Item
_:vb16714678
rdf:type
n3:Context
rdf:value
with microglia. Limited innate antiviral activity may predispose oligodendroglia to be potent responders to IFNγ (Gonzalez et al.,2005; Popko and Baerwald,1999). While there is no evidence supporting toxicity of IFNα/β (Akwa et al.,>>1998<<), more restricted induction of antiviral mediators, especially those also affecting host cell translation, may circumvent apoptosis and guarantee maintenance of critical myelin housekeeping functions and survival.
n3:mentions
n4:9794439
Subject Item
_:vb16714679
rdf:type
n3:Context
rdf:value
Our findings also contradict the hypothesis suggesting that virus initiated IFNα/β production by oligodendroglia drives inflammatory responses during viral‐induced demyelinating disease (Lipton et al.,>>2007<<). The low abundance of PRR at basal levels rather provide a mechanism underlying the apparent paucity of oligodendroglia to express cytokines during multiple sclerosis or other CNS inflammatory conditions (Cannella and Raine,2004; Zeis et
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The low abundance of PRR at basal levels rather provide a mechanism underlying the apparent paucity of oligodendroglia to express cytokines during multiple sclerosis or other CNS inflammatory conditions (Cannella and Raine,>>2004<<; Zeis et al.
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abundance of PRR at basal levels rather provide a mechanism underlying the apparent paucity of oligodendroglia to express cytokines during multiple sclerosis or other CNS inflammatory conditions (Cannella and Raine,2004; Zeis et al.,>>2008<<). Our data thus support the notion that oligodendroglia are defensive players under inflammatory conditions.
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