2012 CXCR2 signaling and host defense following coronavirus-induced encephalomyelitis

2012·0.43 MB·English

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CXCR2 signaling and host defense F R
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following coronavirus-induced t
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encephalomyelitis e

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Brett S Marro1, Martin P Hosking1,2 & Thomas E Lane*1,3,4 r
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1Department of Molecular Biology & Biochemistry, University of California, Irvine CA 92697-3900, USA i
2Department of Immunology & Microbial Sciences, Scripps Research Institute, La Jolla, CA, USA lo e
3Sue & Bill Gross Stem Cell Center, University of California, Irvine CA 92697-3900, USA
4Multiple Sclerosis Research Center, University of California, Irvine CA 92697-3900, USA g
*Author for correspondence: Tel.: [phone] n [email protected] y
w
Inoculation of the neurotropic JHM strain of mouse hepatitis virus (JHMV) into the
CNS of susceptible strains of mice results in widespread replication within glial
cells, accompanied by infiltration of virus-specific T lymphocytes that control the
virus through cytokine secretion and cytolytic activity. The virus persists within
the white matter tracts of surviving mice, resulting in demyelination that is
amplified by inflammatory T cells and macrophages. In response to infection,
numerous cytokines/chemokines are secreted by resident cells of the CNS and
inflammatory leukocytes that participate in both host defense and disease.
Among these are the ELR-positive chemokines that are able to signal through
CXC chemokine receptors including CXCR2. Shortly after JHMV infection,
ELR-positive chemokines contribute to host defense by attracting CXCR2-
expressing cells, including polymorphonuclear cells, to the CNS that aid host
defense by increasing the permeability of the blood–brain barrier. During chronic
disease, CXCR2 signaling on oligodendroglia protects these cells from apoptosis
and restricts the severity of demyelination. This review covers aspects related to
host defense and disease in response to JHMV infection and highlights the
different roles of CXCR2 signaling in these processes.
Mouse hepatitis virus (MHV) is a large n Characterizing mechanisms associated with
(30–32 kb), enveloped ssRNA virus that is a viral-induced immune-mediated demyelina-
member of the Coronaviridae family in the order tion;
Nidovirales [1]. These viruses include a variety of
n Developing novel approaches to promote
strains that can induce wide-ranging patholo-
remyelination within the context of persistent
gies dependent on age, strain and route of infec-
viral infection of the CNS.
tion. Examples include the hepatotropic MHV-2
strain which leads to fulminant hepatitis follow-
ing intraperitoneal (ip.) injection, but is weakly JHMV-induced acute encephalomyelitis
neurotropic, causing only mild acute meningitis Following a sublethal ic. infection with the
following intracranial (ic.) inoculation [2]. By neuroadapted JHMV, the virus infects and
contrast, ic. infection of susceptible mice with replicates within ependymal cells lining the lat-
the dual neurotropic and hepatotropic A59 strain eral ventricles [6]. Within 24 h, JHMV rapidly
results in infection of neurons and glial cells spreads and penetrates further into the paren-
within the CNS, resulting in a mild encephalo- chyma, where astrocytes, oligodendrocytes and
myelitis, limited demyelination and hepatitis microglia are targets of infection [6,7]. The virus
[3,4]. The JHM strain of MHV (JHMV), a well- also disseminates to the spinal cord through
characterized laboratory strain that was initially cerebrospinal fluid, targeting ependymal cells
serially passaged in suckling mouse brains to prior to spreading to glial cells of the white
produce a highly neurovirulent virus, can cause matter tracts [6]. Viral titers within the brain
severe encephalomyelitis and demyelination in peak between days 5–7 postinfection (p.i.) Keywords
adult mice [5]. Infection of susceptible mice with and decline below levels of detection by plaque
n chemokine receptors
neuroattenuated variants of JHMV have yielded assay (~100 PFU/g tissue) between 10–14 days
n chemokines n CNS
useful surrogate mouse models for: p.i. [8]. However, clearance is incomplete and n demyelination
viral antigens and RNA are capable of persist- n encephalomyelitis n virus
n Viral-induced encephalomyelitis;
ing within the CNS [9], and this is associated
n Defining molecular mechanisms governing with chronic neuroinflammation leading to an
neuroinflammation; immune-mediated demyelinating disease with part of
10.2217/FVL.12.23 © 2012 Future Medicine Ltd Future Virol. (2012) 7(4), 349–359 ISSN 1746-0794 349
Review Marro, Hosking & Lane
clinical and histologic similarities to the human chemokines CXCL9, CXCL10 and CCL5 [25–30].
demyelinating disease multiple sclerosis. Evidence for this is supported by chemokine
An innate antiviral response is triggered neutralization studies where administration of
following JHMV infection, characterized anti-CXCL10 or anti-CCL5 blocking antibodies
by increased expression of proinflammatory during acute JHMV infection prevented early
cytokines and chemokines, along with matrix CD4+ and CD8+ T-cell infiltration to the CNS
metalloproteinases (MMPs) [10,11]. A cytokine [26–29]. Similarly, JHMV infection of CXCL10-
milieu consisting of IL-1a, IL-1b, IL-6, IL-12 deficient mice limited entry of CD4+ and CD8+
and TNF-a is detected within the CNS during T cells into the CNS, resulting in significantly
the first 48 h following JHMV infection [12,13]. higher viral titers at day 12 p.i. [31]. By contrast,
Type I IFN-a and IFN-b are also detected early treatment with anti-CXCL10 antisera in mice
in response to JHMV infection, suggesting an persistently infected with the virus, in which
important role in host defense. Indeed, elegant demyelination is established, selectively inhibited
studies by Bergmann and colleagues showed virus-specific CD4+ T cells, but not virus-specific
an increase in viral spread and mortality in CD8+ T-cell trafficking into the CNS, resulting
JHMV-infected IFNAR-/- mice, while exog- in a dramatic improvement in motor skills [32,33].
enous treatment of mice with either sort of type I Blocking CXCR3, the receptor for CXCL10, also
IFN limits viral replication and dissemination negatively impacts CD4+ T-cell recruitment to
[14–16]. In addition to directly inhibiting viral the CNS, while the trafficking of CD8+ T cells
replication, type I IFNs are believed to enhance is not significantly impacted [26]. Follow-up
antigen presentation via increased MHC class I studies further support the role of CXCL10 in
expression, helping to link innate and adaptive promoting T-cell migration following JHMV
immune responses [17]. infection, but not in enhancing T-cell antiviral
Cellular components of the innate immune effector functions [34]. These findings argue for
response consist of neutrophils, natural killer the differing roles of CXCL10 in mediating traf-
(NK) cells and monocytes/macrophages that ficking of CXCR3-bearing T cells into the CNS
rapidly migrate to the CNS in response to in response to JHMV infection. This is dictated,
JHMV infection. Although these cells were ini- in part, by the stage of the disease, such as acute
tially not considered important in host defense, versus chronic. One potential explanation for
this opinion has been revised based upon recent these findings may lie in the different trafficking
studies that have more carefully examined their patterns of T cells during chronic disease, as well
functional contributions. Both neutrophils and as evidence indicating that virus-specific CD8+
monocyte/macrophages are now thought to T cells are retained within the CNS during per-
contribute to the permeabilization of the blood– sistence [35]. Importantly, other chemokines exert
brain barrier (BBB) through secretion of MMPs, a chemotactic effect on T cells, macrophages
which is critical for allowing access of virus-spe- and other inflammatory cells following JHMV
cific T cells into the CNS [18–22]. With regards infection. Adoptive transfer studies indicate that
to NK cells, Trifilo et al. demonstrated that NK CCR5-deficient CD4+ T cells transferred into
cells can contribute to control of viral replica- JHMV-infected RAG1-/- mice display a muted
tion following the infection of immunodeficient ability to traffic to the CNS [36]. However, adop-
mice with a recombinant JHMV engineered to tive transfer of CCR5-/- CD8 T cells can infiltrate
express the chemokine CXCL10 [23]. However, into the CNS in infected RAG1-deficient mice,
a more relevant study evaluating the functional further demonstrating that different signaling
contributions of NK cells to host defense in cues control CD4+ and CD8+ T-cell migra-
response to JHMV infection was provided by tion during acute JHMV infection [37]. Genetic
Zuo et al., in which IL-15-deficient mice that ablation of CCR2, but not the signaling ligand
lacked NK cells were shown to control JHMV CCL2, results in increased mortality associated
replication within the CNS as efficiently as wild- with impaired ability to control JHMV replica-
type mice and effectively argue that NK cells are tion within the brain, and this correlated with
dispensable with regard to effectively controlling the limited infiltration of virus-specific T cells
JHMV replication during acute disease [24]. into the CNS [38]. CCR2 has been demonstrated
JHMV-specific CD4+ and CD8+ T cells to be critical in regulating BBB permeability by
presumably expand to viral antigens presented signaling through the receptor expressed on
within draining cervical lymph nodes, traffick- endothelial cells in other neuroinflammatory
ing into the CNS through a permeable BBB in disease models, suggesting that CCR2 signal-
response to chemotactic signals including the ing influences leukocyte access to the CNS by
350 Future Virol. (2012) 7(4) future science group
CXCR2 signaling & host defense following coronavirus-induced encephalomyelitis Review
controlling BBB integrity in response to JHMV Indeed, virus-specific Tregs dampen prolifera-
infection [39]. However, both CCL2 and CCR2 tion of virus-specific effector CD4+ T cells, and
promote macrophage accumulation within the depletion of Tregs increases mortality [52,53].
CNS of infected mice [38]. Follow-up studies con- These data suggest that within the context of
firmed the importance of CCL2 in mediating acute JHMV-induced neurological disease,
monocyte/macrophage recruitment to the CNS Tregs limit immunopathological disease without
of JHMV-infected mice [20,40]. negatively impacting viral clearance [52].
Antiviral effector mechanisms associated
with viral clearance within the CNS include the JHMV-induced demyelination
upregulation of MHC class I and MHC class II A hallmark feature of JHMV infection of the
on antigen-presenting cells following secretion CNS occurs following the acute stage of disease,
of IFN-g by both CD4+ and CD8+ T cells, as in which the virus has spread into the spinal
well as perforin-mediated cytolysis of astrocytes cord where it infects astrocytes and oligoden-
and microglia by virus-specific CD8+ T cells droglia. As a result, the virus persists as non-
[8,41,42]. Upon JHMV infection of the CNS, infectious RNA and animals develop demyelin-
CD4+ T cells promote CD8+ T-cell expansion ating lesions within the brain and spinal cord
within the periphery and aid in enhancing anti- that are associated with clinical manifestations
viral effector functions [43]. Depletion of CD4+ including awkward gait and hindlimb paralysis.
T cells diminishes CD8+ T-cell-mediated control Current evidence suggests that demyelination in
of viral replication within the CNS, which is JHMV-infected mice is not the result of epitope
associated with reduced expression of IFN-g and spreading and induction of an immune response
granzyme B, and elevated CD8+ T-cell apopto- against neuroantigens, as has recently been
sis [43]. These results support and extend earlier reported to occur during Theiler’s virus-induced
studies indicating that CD4+ T cells play a cen- demyelination [54,55]. However, adoptive trans-
tral role in both enhancing peripheral activation fer of T cells from JHMV-infected rats to naive
of CD8 T cells and prolonging their antiviral recipients results in demyelination [56]. Whether
function within the CNS, and further suggest a similar response occurs in MHV-infected mice
that IL-21 may be a critical factor in mediating and what the contributions are to demyelination
these effects [43–45]. Infected oligodendrocytes are unknown at this time. A recent report has
appear to be resistant to the cytolytic effector suggested that infection with MHV strain A59
functions of CD8+ T cells, but instead control promotes the activation of autoreactive T cells
JHMV replication through IFN-g signaling specific to myelin basic protein, although the
generated from virus-specific T cells [41,42,46,47]. contributions of these cells to demyelination
The potent antiviral response reduces viral rep- are undefined [57].
lication to below detectable levels (as defined Oligodendrocytes are an important viral
by plaque assays) between days 10–14 p.i., but reservoir during chronic disease [6,7]; however,
sterile immunity does not occur; viral RNA and viral-induced lysis of oligodendrocytes is not
antigens persist and are sequestered primarily considered to be a primary mechanism contrib-
within white matter tracts, and this is accom- uting to demyelination, since JHMV-infection
panied by the presence of activated glial cells of immunodeficient mice (e.g., those lacking
and retention of virus-specific CD4+ and CD8+ thymically-educated T and B lymphocytes)
T cells [8,9,48]. Neutralizing JHMV-specific anti- results in widespread viral replication within
body is detected during chronic disease and is oligo dendrocytes with very limited demy-
critical in preventing viral recrudescence [49–51]. elination [58]. Moreover, adoptive transfer of
More recently, Perlman and colleagues have splenocytes from MHV-immunized immuno-
provided important insight into the functional competent mice into JHMV-infected immuno-
role of Tregs during acute JHMV-induced CNS deficient mice results in robust demyelination,
disease [52,53]. Tregs are detected within the CNS implicating T cells as mediators of white matter
at the same time as effector CD4+ T cells, indi- damage [58–60]. Additionally, JHMV-infected
cating that the emergence and accumulation of CD4-/- or CD8-/- mice develop demyelination
both populations of cells is on a similar timeline demonstrating the importance of both T-cell
following viral infection. Furthermore, virus- subsets in contributing to neuropathology,
specific Tregs express both IFN-g and IL-10, although JHMV-infected CD4-/- mice exhibited
suggesting that they have immune regulatory a diminished severity of myelin loss in the white
properties that are mediated, in part, by cyto- matter tracts of the spinal cord compared with
kines secreted following antigen stimulation. infected CD8-/- mice, suggesting an important
future science group www.futuremedicine.com 351
Review Marro, Hosking & Lane
role for CD4+ T cells in amplifying disease sensitivity of oligodendrocyte progenitor cells
progression [29]. One possible mechanism by (OPCs) to IFN-g-induced apoptosis when com-
which CD4+ T cells accelerate demyelination pared with mature oligodendrocytes, illustrat-
is through secretion of the chemokine CCL5, a ing that susceptibility to IFN-g-induced death
potent chemoattractant for inflammatory mac- is controlled, in part, by the maturation state
rophages [29]. Macrophages have been shown to of the cell [69–74]. Interestingly, demyelination
be important in development of demyelinating is observed within JHMV-infected mice in
lesions within spinal cord white matter during which the IFN-g receptor is selectively ablated
chronic JHMV infection [58,61]. Furthermore, in oligodendrocyte lineage cells, suggesting that
CCL5 neutralization or the genetic ablation demyelination is multifaceted and that addi-
of CCR5 is associated with reduced macro- tional mechanisms, including the local release
phage infiltration correlating to a reduction in of chemokines such as CXCL10 from activated
demyelination [62,63]. An alternate view is that resident glia, may directly contribute to dysregu-
the CD8+ T cells also enhance demyelination lation of oligodendrocyte function and/or death
through the release of IFN-g, and that this [46,75,76]. Early studies also implicated the release
promotes the migration and accumulation of of nitric oxide (NO) from activated inflamma-
activated macrophages/microglia within white tory macrophages and resident microglia as
matter tracts of JHMV-infected mice [64]. Other a factor involved in inducing demyelination
studies argue for a more protective role for CD4+ [76]. Treatment of JHMV-infected mice with
T cells through IFN-g-mediated control of viral aminoguanidine, a selective inhibitor of NOS2,
replication and/or additional undefined mecha- diminished clinical disease severity, and this
nisms [65,66]. Bystander CD4+ T cells, for exam- was associated with reduced neuroinflammation
ple, activated but not specific for viral antigens, and demyelination implying a potential role of
are also thought to not be involved in white NOS2-derived NO in regulating proinflamma-
matter damage in JHMV-infected mice [67]. tory gene expression within the CNS of infected
Providing additional insight into how T cells mice [76]. However, genetic ablation of NOS2
contribute to either disease or defense are stud- did not dampen demyelination in response to
ies from Trandem et al. showing that adoptive JHMV infection when compared with wild-
transfer of Tregs to JHMV-infected mice atten- type control mice, indicating that NO does not
uates clinical disease severity, and that this is contribute to myelin damage [77,78]. Differences
associated with dampened neuroinflammation may relate to off-target effects of aminoguani-
and demyelination [68]. Clearly, T-cell infiltra- dine that, in addition to muting NOS2 activity,
tion into the CNS of mice persistently infected also alter gene expression of specific chemokine
with JHMV is important in the pathogenesis genes within resident glial cells.
of disease, although unifying mechanism(s)
explaining how these cells contribute to disease Neutrophils, BBB breakdown & CXCR2
progression as well as protection remain elusive, signaling during acute JHMV-induced
a fact most likely a consequence of the different disease
model systems used to evaluate functional roles Polymorphonuclear neutrophils (PMNs) can
for T-cell subsets. infiltrate into the CNS within 24 h p.i. follow-
Although the infectious virus is cleared by ing ic. inoculation with JHMV where they are
day 12 p.i., IFN-g secretion from activated thought to carry out critical effector functions
T lymphocytes can be detected within the in host defense, including the release of MMP9
brain for up to 4 weeks p.i. and likely contrib- from stored granules [22,79]. Their rapid migration
utes to the deleterious effects on oligodendro- to the luminal side of the perivascular space cor-
cytes during the chronic stage of the disease relates with degradation of the basal lamina and
[12]. Early studies have shown that the adop- extracellular matrix of the BBB, thus enhancing
tive transfer of enriched CD8+ T cells obtained inflammation by facilitating the extravasation of
from JHMV-sensitized IFN-g-deficient mice monocytes and leukocytes into the parenchyma
into JHMV-infected RAG1-/- mice resulted in [19,21,80–82]. The importance of neutrophils in host
less severe demyelination compared with the defense following JHMV infection was initially
transfer of IFN-g-expressing CD8+ T cells, highlighted by Stohlman and colleagues demon-
implicating CD8+ T-cell-derived IFN-g as an strating that there is an increase in viral burden
important contributor to demyelination via and mortality of neutropenic mice infected with a
destruction/damage to oligodendroglia [64]. lethal variant of JHMV [22]. This correlated with
Numerous groups have demonstrated increased a lack of detectable MMP9 within CNS extracts
352 Future Virol. (2012) 7(4) future science group
CXCR2 signaling & host defense following coronavirus-induced encephalomyelitis Review
and only minor disruption of the BBB, indicating by impairing monocyte recruitment to the CNS
a protective role for neutrophils during the early through genetic ablation of CCR2, there is the
stages of lethal JHMV infection [22]. retention of leukocytes within the perivascular
The ELR-positive chemokines CXCL1 and space of the CNS, corresponding to a reduction
CXCL2 in mice (and CXCL8 in humans), delin- in neuro inflammation [20]. This occurs regard-
eated by a ELR (glutamic acid–leucine–arginine) less of neutrophil activity at the BBB and further
amino acid sequence preceding a group of con- illustrates the complexity of early events leading
served cysteine residues (CXC) at the amino to the breakdown of the BBB following JHMV
termini of the molecules, are potent chemoat- infection [20].
tractants for neutrophils expressing the cognate Neutrophil effector activity has also been
chemokine receptor CXCR2. Indeed, CXCL1 shown to have critical roles in other CNS-based
overexpression from oligodendrocytes within the viral infections. Depletion of PMNs following
CNS of naive transgenic mice results in rapid the infection of susceptible mice with West
neutrophil accumulation into the perivascular, Nile virus (WNV) leads to higher viremia and
meningeal and parenchymal areas of the brain reduced survival suggesting a protective role for
[83]. CXCL1 and CXCL2 mRNA transcripts are these cells [86]. Indeed, Bai et al. demonstrated
upregulated within the brain and spinal cord by that infection of CXCR2-deficient mice with
day 3 p.i. in JHMV-infected mice, with CXCL1 WNV results in higher viremia at day 5 p.i. [86].
protein expression appearing to colocalize with However, one caveat to this study is that neutro-
reactive astrocytes [19,82]. Similar to the results of phils may be a viral reservoir for WNV, and the
neutropenic mice infected with JHMV, block- lack of neutrophil accumulation within the brains
ing neutrophil recruitment to the CNS through of CXCR2-/- mice results in lower viremia shortly
antibody-mediated neutralization of the ligand after inoculation with WNV. Nonetheless, neu-
domain of CXCR2 during sublethal JHMV trophils were shown to be important in host
infection leads to a significant increase in mortal- defense against WNV. Conversely, McGavern
ity and the inability to control virus replication and colleagues showed a detrimental effect of
[19]. This is associated with over a 50% reduction neutrophil activity following infection with the
in leukocytes infiltrating into the CNS, which mouse-adapted Armstrong strain of lympho-
correlated with an intact BBB and demonstrates cytic choriomeningitis virus, where it was dem-
a critical role for ELR-positive chemokines in onstrated that cytotoxic CD8+ T cells promote
shaping the adaptive immune response to JHMV neutrophil accumulation at the BBB, leading to
[19]. Curiously, host defense against JHMV a loss of vascular integrity that results in fatal
infection in CXCR2-deficient mice contradicts encephalitis [87]. Moreover, silencing of CXCR2
the CXCR2 neutralization studies, as CXCR2- through antibody blockade or genetic ablation
deficient mice infected with JHMV have no has been shown to dampen inflammation and
deficits in survival, viral clearance or BBB deg- tissue injury in models in which neutrophil infil-
radation [19]. Although reduced in numbers, neu- tration correlates with disease initiation, such as
trophils were still detected within the CNS of inflammation-mediated injury to the lung [88–90]
JHMV-infected CXCR2 -/- mice indicating that and during experimental bacterial infections
their migration may be the result of induction of within the brain [91].
compensatory receptors that may promote their Emerging evidence also suggests that
chemotaxis, such as CXCR1 [19,84]. Furthermore, CXCR2-bearing neutrophils are necessary to
recent evidence has demonstrated that MMP promote CNS-based autoimmune disorders
secretion from neutrophils is not essential for in mice [92,93]. Willenborg and colleagues first
promoting inflammation, since JHMV-infected demonstrated that antibody depletion of PMNs
MMP9-/- mice show similar BBB permeability could dampen the clinical severity of early
and subsequent leukocyte infiltration compared effector phases of experimental autoimmune
with infected MMP9+/+ controls. This indicates encephalomyelitis (EAE) following immuni-
that MMP9 is dispensable for BBB disruption, zation with encephalitogenic myelin peptides
and that compensatory mechanisms to pro- [94]. Furthermore, CXCL1 and CXCL2 are
mote BBB permeability exist, such as enhanced upregulated within the CNS during chronic
MMP-3 secretion from resident glia [85]. In addi- EAE disease and genetic ablation or antibody
tion to MMP9 secretion by neutrophils, it is also blockade of CXCR2 within mice resulted in the
feasible that these cells can influence MMP pro- failure to develop EAE. Also, adoptive transfer
duction by resident cells of the CNS. Finally, of CXCR2-expressing PMNs into CXCR2-/-
Bergmann and colleagues demonstrated that, mice re-established EAE disease, although with
future science group www.futuremedicine.com 353
Review Marro, Hosking & Lane
slightly reduced severity [92,93]. Using a cupr- results of this study remain enigmatic due to
izone-induced demyelinating disease model, the difficulty in defining the exact mechanism
Liu et al. discovered that neutrophils are neces- by which CXCL1 leads to the observed effects,
sary to induce demyelination following cuprizone as overexpression of CXCL1 could desensitize
treatment, but that CXCR2-deficient mice were CXCR2 signaling on neutrophils and negatively
resistant to demyelination even though these impact their migration to the CNS [110].
cells accumulated within the CNS, implicating With regard to a protective role for CXCR2
aberrant effector functions in CXCR2-/- neu- in preventing cells from an oligodendrocyte
trophils [95]. Together, these findings highlight lineage from death during JHMV infection, we
a role of ELR-positive chemokines in initiating have recently demonstrated that administration
and amplifying inflammation within the CNS of a blocking antibody specific for CXCR2 to
in response to infection with a neurotropic virus JHMV-infected mice increases clinical disease
and sensitization to encephalitogenic myelin pep- severity, and that this correlates with a signifi-
tides by enhancing migration, accumulation and cant increase in oligodendrocyte apoptosis and
effector functions of neutrophils. demyelination [82]. Furthermore, JHMV infec-
tion of cultured OPCs derived from mouse neu-
Neuroprotective effects of ELR-positive ral progenitor cells results in apoptosis, and this
chemokine signaling during chronic is blocked following inclusion of the CXCL1
JHMV-induced disease [82]. The protective effect of CXCR2 signaling
Oligodendrocytes appear to be refractory to also extends to IFN-g-induced apoptosis of cul-
JHMV-induced apoptosis in vivo, suggesting tured OPCs, as the addition of CXCL1 to IFN-
that a signaling pathway could be triggered in g-treated cultures restricts cell death [75]. Our
oligodendrocytes that could act to protect them findings suggest that one mechanism by which
against JHMV-induced death and limit the IFN-g induces OPC death is through induction
severity of demyelination [58]. Recent studies have of CXCL10 that subsequently signals through
shown that activation of the PI3K/Akt signal- CXCR3 [75]. Highlighting the importance of
ing pathway, through stimulation of the tyrosine CXCL10 in enhancing IFN-g-mediated cell
kinase family of receptors on oligodendrocytes, death is the demonstration of reduced apopto-
enhances their survival when treated with pro- sis in IFN-g-treated OPC cultures derived from
apoptotic TNF-a [96,97]. In addition, CXCR2 CXCR3-/- mice [75]. This observation supports
signaling may have beneficial roles that extend and extends other studies demonstrating that
beyond its influence on promoting chemotaxis CXCL10 promotes neuronal apoptosis dur-
towards ELR-positive chemokine gradients. ing SIV-induced encephalitis [111] and WNV-
CXCR2 is expressed on a variety of CNS cell induced encephalitis [112–114]. Furthermore,
subsets, including neurons [98,99], astrocytes [100], the significance of CXCR2 signaling to OPC
microglia [101] and cells of the oligodendrocyte protection from IFN-g and CXCL10-mediated
lineage [75,82,102]. Human CXCL8 – a ligand cell death is further supported by the finding
for CXCR2 – provides a neurotrophic effect on that CXCR2-deficient OPCs are resistant to the
cultured hippocampal and cerebellar granule tonic effects of CXCL1 in response to treatment
neurons during in vitro viability assays [103,104], with either IFN-g or CXCL10. Mechanisms
and also blocks Fas-mediated apoptosis of cul- associated with CXCR2-mediated protection in
tured astrocytes [105]. Furthermore, cultured these findings include reduced activation of the
mouse OPCs proliferate in response to CXCL1 proapoptotic caspase 3 and increased expression
secreted from spinal cord astrocytes [106], while of the anti-apoptotic Bcl-2 in CXCL1-treated
the CXCL1/CXCR2 signaling system is associ- cultures [75].
ated with the proliferation of human fetal OPCs
[107] and OPC positioning and proliferation Conclusion
within the developing mouse spinal cord [108]. The JHMV-induced model of encephalo myelitis
Finally, Omari et al. have described a potential provides an important tool for interrogating mech-
protective effect of CXCL1 overexpression during anisms associated with the initiation and persis-
EAE [109]. Using a doxycycline-inducible trans- tence of neuroinflammation and demyelination in
genic mouse system, the authors revealed that response to viral infection of the CNS. Ongoing
astrocyte-specific CXCL1 overexpression follow- research in our laboratory continues to focus on
ing the induction of EAE reduces clinical severity the role of ELR-positive chemokine signaling on
and is associated with diminished demyelination oligodendroglia during JHMV-induced neuro-
and enhanced remyelination [64]. However, the inflammation. It will be important to analyze the
354 Future Virol. (2012) 7(4) future science group
CXCR2 signaling & host defense following coronavirus-induced encephalomyelitis Review
effects of selectively ablating CXCR2 on oligo- as the CXCR2 signaling axis has the potential
dendroglia during JHMV-induced demyelination to limit myelin loss and potentiate axonal spar-
and also to identify and manipulate the cellular ing and remyelination in human demyelinating
sources of ELR-positive chemokines in the CNS diseases such as multiple sclerosis [102,115].
that may contribute to neuroprotection during
chronic JHMV-induced disease. Financial & competing interests disclosure
This work was funded by National Institutes of Health
Future perspective (NIH) Grant R01 NS041249 and a Collaborative
Explicit mechanisms by which PMNs and MMPs Center Research Award (CA1058-A-8) from the
govern the breakdown of the BBB to promote National Multiple Sclerosis Society to TE Lane.
the infiltration of inflammatory leukocytes in BS Marro was supported by the NIH Virology Training
response to viral infection of the CNS remain to Grant 5T32AI007319. The authors have no other rel-
be characterized. Answers to these questions will evant affiliations or financial involvement with any
provide further insights into pathological mecha- organization or entity with a financial interest in or
nisms that will allow a better understanding of financial conflict with the subject matter or materials
inflammatory events surrounding viral encepha- discussed in the manuscript apart from those disclosed.
litis in humans. Moreover, uncovering potential No writing assistance was utilized in the production
endogenous neuroprotective mechanisms such of this manuscript.
Executive summary
Initiation of an acute antiviral cellular response to the JHM strain of mouse hepatitis virus infection occurs following
efficient breakdown of the blood–brain barrier
n Neutrophil‑specific MMP9 secretion on the luminal side of the blood–brain barrier (BBB) and astrocyte‑specific MMP3 secretion on
the parenchymal side of the BBB degrade the basement membrane and extracellular matrix, facilitating leukocyte migration into
the CNS.
n The specific enzymatic role of each matrix metalloproteinase is still unclear due to compensatory mechanisms that arise following
genetic ablation of individual matrix metalloproteinases.
n It remains to be determined if neutrophils can execute other proinflammatory effector functions in promoting host defense to the
JHM strain of mouse hepatitis virus (JHMV).
JHMV-induced chronic demyelinated disease is amplified by activated virus-specific T cells & macrophages/microglia
n IFN‑g secretion by activated virus‑specific CD4+ and CD8+ T cells contributes to damage to cells of an oligodendrocyte lineage and
enhances proinflammatory cytokine/chemokines secretion from inflammatory macrophages as well as resident glia.
The CXCR2–CXCL1 signaling chemokine system may have neuroprotective effects on cells of the oligodendrocyte lineage
following JHMV-induced chronic disease
n Astrocyte‑specific expression of CXCL1 may promote antiapoptotic effects on oligodendroglia, as CXCR2 neutralization during
chronic JHMV‑induced disease results in increased disease severity correlating with increased numbers of apoptotic oligodendrocytes
and oligodendrocyte progenitor cells.
n IFN‑g‑induced expression of CXCL10 promotes apoptosis of cultured oligodendrocyte progenitor cells through signaling via the
CXCR3 receptor. This can be blocked through tonic effect of CXCL1 by preventing cleavage of caspase‑3 and increasing expression
of Bcl‑2.
n Oligodendrocyte‑specific ablation of CXCR2 during chronic JHMV‑induced disease will provide further insights into potential
endogenous protective mechanisms of ELR‑positive chemokine signaling.
produced by the A59 strain of mouse hepatitis cells by the murine hepatitis virus JHM strain
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