A protective role for ELR+ chemokines during acute viral encephalomyelitis.
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.
Hosking
Martin P
MP
Department of Molecular Biology and Biochemistry, University of California, Irvine, California, USA.
Liu
Liping
L
Ransohoff
Richard M
RM
Lane
Thomas E
TE
D000208:Acute Disease; D000818:Animals; D001923:Brain Chemistry; D054360:Chemokine CXCL1; D054426:Chemokine CXCL2; D054365:Chemokine CXCL5; D019743:Chemokines, CXC / Q000096:biosynthesis / Q000276:immunology*; D004679:Encephalomyelitis / Q000276:immunology* / Q000821:virology*; D051379:Mice; D018345:Mice, Knockout; D006517:Murine hepatitis virus; D020556:Neutrophil Infiltration / Q000276:immunology; D023063:Receptors, Interleukin-8B / Q000172:deficiency / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology; D014779:Virus Replication
D054360:Chemokine CXCL1; D054426:Chemokine CXCL2; D054365:Chemokine CXCL5; D019743:Chemokines, CXC; D023063:Receptors, Interleukin-8B