UC Irvine

The functional role of ELR-positive CXC chemokines in host defense during acute viral-induced encephalomyelitis was determined. Inoculation of the neurotropic JHM strain of mouse hepatitis virus (JHMV) into the central nervous system (CNS) of mice resulted in the rapid mobilization of PMNs expressing the chemokine receptor CXCR2 into the blood. Migration of PMNs to the CNS coincided with increased expression of transcripts specific for the CXCR2 ELR-positive chemokine ligands CXCL1, CXCL2, and CXCL5 within the brain. Treatment of JHMV-infected mice with anti-CXCR2 blocking antibody reduced PMN trafficking into the CNS by >95%, dampened MMP-9 activity, and abrogated blood-brain-barrier (BBB) breakdown. Correspondingly, CXCR2 neutralization resulted in diminished infiltration of virus-specific T cells, an inability to control viral replication within the brain, and 100% mortality. Blocking CXCR2 signaling did not impair the generation of virus-specific T cells, indicating that CXCR2 is not required to tailor anti-JHMV T cell responses. Evaluation of mice in which CXCR2 is genetically silenced (CXCR2−/− mice) confirmed that PMNs neither expressed CXCR2 nor migrated in response to ligands CXCL1, CXCL2, or CXCL5 in an in vitro chemotaxis assay. Moreover, JHMV infection of CXCR2−/− mice resulted in an approximate 60% reduction of PMN migration into the CNS, yet these mice survived infection and controlled viral replication within the brain. Treatment of JHMV-infected CXCR2−/− mice with anti-CXCR2 antibody did not modulate PMN migration nor alter viral clearance or mortality, indicating the existence of compensatory mechanisms that facilitate sufficient migration of PMNs into the CNS in the absence of CXCR2. Collectively, these findings highlight a previously unappreciated role for ELR-positive chemokines in enhancing host defense during acute viral infections of the CNS.Author SummaryConsequences of viral infection of the central nervous system (CNS) can range from encephalitis and paralytic poliomyelitis to relatively benign infections with limited clinical outcomes. The localized expression of proinflammatory chemokines within the CNS in response to viral infection has been shown to be important in host defense by attracting antigen-specific lymphocytes from the microvasculature into the parenchyma that control and eventually eliminate the replicating pathogen. However, the relationship between chemokine expression and recruitment of myeloid cells, e.g. neutrophils, to the CNS following infection with a neurotropic virus is not well characterized. Emerging evidence has indicated that the mobilization of neutrophils into the blood and recruitment to the CNS following microbial infection or injury contributes to permeabilization of the blood-brain-barrier that subsequently allows entry of inflammatory leukocytes. Therefore, we have defined the chemokines involved in promoting the directional migration of neutrophils to the CNS in response to viral infection. Using the neurotropic JHM strain of mouse hepatitis virus (JHMV) as a model of acute viral encephalomyelitis, we demonstrate a previously unappreciated role for members of the ELR-positive CXC chemokine family in host defense by attracting PMNs bearing the receptor CXCR2 to the CNS in response to viral infection.