Differential roles for the CXC chemokine receptors in host defense and disease following viral infection of the central nervous system.

摘要

Using neutralizing antibodies, we assessed the roles for the CXC chemokine receptors CXCR3 and CXCR2 during acute and chronic viral encephalomyelitis. Previous work in our laboratory has identified CXCR3 ligands as critical mediators of both host defense during acute infection and demyelination during chronic infection. The precise role for CXCR3 in attracting activated T lymphocytes was however unclear. We observed constitutive expression of CXCR3 upon both subsets of T cells during acute and chronic infection. Neutralization of CXCR3 during acute or chronic infection reduced CD4+ T cell infiltration into the CNS, and neutralization during chronic infection was associated with an improvement in clinical severity and a reduction in demyelination, highlighting the critical role for CXCR3 in T cell trafficking and pathogenesis.;Neutrophils are critical for host defense following viral infection of the CNS. However, the mechanisms by which neutrophils are attracted into the CNS are unclear. During acute infection, mRNA for both CXCR2 and its associated ligands was observed within the brains and spinal cords of infected mice. Moreover, infiltration of CXCR2+ neutrophils into the CNS closely paralleled CXCR2 ligand expression within the brain. Neutralization of CXCR2 during acute infection prevented neutrophil infiltration into the CNS, thereby abrogating efficient degradation of the blood brain barrier. Virus-specific T lymphocytes were unable to enter the CNS, and all mice receiving CXCR2 antiserum experience elevated viral burdens and succumb to viral infection. During chronic viral infection, CXCR2 ligands were preferentially upregulated within the spinal cord. Antibody-mediated targeting of CXCR2 influenced neither viral burden nor cellular infiltration into the CNS. Rather, mice receiving anti-CXCR2 serum had delayed clinical recovery and increased demyelination associated with increased glial cell apoptosis within the white matter of the spinal cord. In vitro, the CXCR2 ligand CXCL1 protected cultured oligodendrocytes from viral induced apoptosis, preventing caspase 3 activation and rescuing Bcl-2 expression. In summary these findings demonstrate the differential protective or pathogenic roles that chemokine receptors play during viral infection of the CNS. Moreover, we describe a novel role for the chemokine receptor CXCR2 as a potent survival signal during chronic viral infection.