Abstract
BackgroundThe functional role of ELR-positive CXC chemokines during viral – induced demyelination was assessed. Inoculation of the neuroattenuated JHM strain of mouse hepatitis virus (JHMV) into the CNS of susceptible mice results in an acute encephalomyelitis that evolves into a chronic demyelinating disease, modeling white matter pathology observed in the human demyelinating disease Multiple Sclerosis.Methodology/Principal FindingsJHMV infection induced the rapid and sustained expression of transcripts specific for the ELR (+) chemokine ligands CXCL1 and CXCL2, as well as their binding receptor CXCR2, which was enriched within the spinal cord during chronic infection. Inhibiting CXCR2 signaling with neutralizing antiserum significantly (p<0.03) delayed clinical recovery. Moreover, CXCR2 neutralization was associated with an increase in the severity of demyelination that was independent of viral recrudescence or modulation of neuroinflammation. Rather, blocking CXCR2 was associated with increased numbers of apoptotic cells primarily within white matter tracts, suggesting that oligodendrocytes were affected. JHMV infection of enriched oligodendrocyte progenitor cell (OPC) cultures revealed that apoptosis was associated with elevated expression of cleaved caspase 3 and muted Bcl-2 expression. Inclusion of CXCL1 within JHMV infected cultures restricted caspase 3 cleavage and increased Bcl-2 expression that was associated with a significant (p<0.001) decrease in apoptosis. CXCR2 deficient oligodendrocytes were refractory to CXCL1 mediated protection from JHMV – induced apoptosis, readily activating caspase 3 and down regulating Bcl-2.Conclusion/SignificanceThese findings highlight a previously unappreciated role for CXCR2 signaling in protecting oligodendrocyte lineage cells from apoptosis during inflammatory demyelination initiated by viral infection of the CNS.
Highlights
How chemokine receptor signaling contributes to chronic neurologic diseases has largely been considered within the context of targeted leukocyte recruitment into the CNS [1]
To investigate the role of CXCR2 signaling during chronic – viral encephalomyelitis, C57BL/6 mice were intracerebrally (i.c.) inoculated with JHM strain of mouse hepatitis virus (JHMV), and the mRNA expression pattern of CXCR2, as well as its associated ELR+ chemokines CXCL1, CXCL2, and CXCL5, was assessed within the spinal cord, the primary site of demyelination during chronic disease
The prolonged and elevated expression of the CXCR2 ligands CXCL1 and CXCL2 mRNA throughout the course of JHMV infection within the spinal cord, coupled with the localized CXCL1 expression within spinal cord white matter, implicate a potential role for CXCR2 signaling in host defense during chronic JHMV infection
Summary
How chemokine receptor signaling contributes to chronic neurologic diseases has largely been considered within the context of targeted leukocyte recruitment into the CNS [1]. Numerous resident cell types of the CNS express chemokine receptors under non-inflammatory and inflammatory conditions (reviewed in [2,3]), indicating that these cells are capable of responding to specific chemokine ligands. Chemokine signaling may participate in either repair and/or exacerbation of pathology following insult, injury, or infection of the CNS [4,5,6]. CXCR2, the receptor for the murine ELR+ CXC chemokine ligands CXCL1,22,23, 25, 26 and 27, has been detected either in vitro or in vivo upon resident cells of the CNS, including oligodendrocyte precursor cells (OPC) [7,8,9,10,11,12]. Inoculation of the neuroattenuated JHM strain of mouse hepatitis virus (JHMV) into the CNS of susceptible mice results in an acute encephalomyelitis that evolves into a chronic demyelinating disease, modeling white matter pathology observed in the human demyelinating disease Multiple Sclerosis
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