title: TNF-alpha-dependent regulation of CXCR3 expression modulates neuronal survival during West Nile virus encephalitis.
abstract: The chemokine CXCL10 exerts antiviral effects within the central nervous system (CNS) through the recruitment of virus-specific T cells. However, elevated levels of CXCL10 may induce neuronal apoptosis given its receptor, CXCR3, is expressed by neurons. Using a murine model of West Nile virus (WNV) encephalitis, we determined that WNV-infected neurons express TNF-alpha, which down-regulates neuronal CXCR3 expression via signaling through TNFR1. Down-regulation of neuronal CXCR3 decreased CXCL10-mediated calcium transients and delayed Caspase 3 activation. Loss of CXCR3 activation, via CXCR3-deficiency or pretreatment with TNF-alpha prevented neuronal apoptosis during in vitro WNV infection. These results suggest that neuronal TNF-alpha expression during WNV encephalitis may be an adaptive response to diminish CXCL10-induced death.
authors.affiliation: Division of Infectious Diseases, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Bo
authors.initials: B
authors.lastname: Zhang
authors.forename: Jigisha
authors.initials: J
authors.lastname: Patel
authors.forename: Michelle
authors.initials: M
authors.lastname: Croyle
authors.forename: Michael S
authors.initials: MS
authors.lastname: Diamond
authors.forename: Robyn S
authors.initials: RS
authors.lastname: Klein
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000276:immunology; D002470:Cell Survival / Q000276:immunology; D002478:Cells, Cultured; D015536:Down-Regulation / Q000276:immunology; D005260:Female; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009474:Neurons / Q000276:immunology* / Q000473:pathology* / Q000821:virology; D054367:Receptors, CXCR3 / Q000096:biosynthesis*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000502:physiology*; D014901:West Nile Fever / Q000276:immunology* / Q000473:pathology* / Q000821:virology
chemical_list: C515188:Cxcr3 protein, mouse; D054367:Receptors, CXCR3; D014409:Tumor Necrosis Factor-alpha