TNF-α-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-α, 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-α prevented neuronal apoptosis during in vitro WNV infection. These results suggest that neuronal TNF-α expression during WNV encephalitis may be an adaptive response to diminish CXCL10-induced death.