CXCR2 signaling protects oligodendrocytes and restricts demyelination in a mouse model of viral-induced demyelination.
BACKGROUND
The 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.


RESULTS
JHMV 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.


CONCLUSIONS
These 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.
Hosking
Martin P
MP
Department of Molecular Biology and Biochemistry, University of California Irvine, Irvine, California, United States of America.
Tirotta
Emanuele
E
Ransohoff
Richard M
RM
Lane
Thomas E
TE
D000818:Animals; D017209:Apoptosis; D054360:Chemokine CXCL1 / Q000378:metabolism; D054426:Chemokine CXCL2 / Q000378:metabolism; D004195:Disease Models, Animal; D008024:Ligands; D051379:Mice; D008810:Mice, Inbred C57BL; D009103:Multiple Sclerosis / Q000378:metabolism / Q000473:pathology* / Q000821:virology; D006517:Murine hepatitis virus / Q000502:physiology*; D009836:Oligodendroglia / Q000378:metabolism* / Q000473:pathology; D016133:Polymerase Chain Reaction; D023063:Receptors, Interleukin-8B / Q000378:metabolism*; D015398:Signal Transduction; D015854:Up-Regulation
D054360:Chemokine CXCL1; D054426:Chemokine CXCL2; D008024:Ligands; D023063:Receptors, Interleukin-8B