Double-stranded RNA induces iNOS gene expression in Schwann cells, sensory neuronal death, and peripheral nerve demyelination

Abstract

Inflammation in the peripheral nervous system (PNS) is one of the characteristics of virus-induced peripheral neuropathy. In this inflammatory response, Schwann cells are actively involved. Previously, toll-like receptor 3 (TLR3) was reported as a receptor for double-stranded RNA (dsRNA) that induces antiviral and inflammatory responses in cells of the innate immune system. In this study, we investigated the expression and putative role of TLR3 in Schwann cells. TLR3 was constitutively expressed in Schwann cells. Stimulation with polyinosinic-polycytidylic acid, a synthetic dsRNA analogue, induced the expression of inducible nitric oxide synthase (iNOS) gene in Schwann cells. Studies on the intracellular signal transduction pathways using iSC, an immortalized Schwann cell line, revealed that dsRNA induces the activation of NF-B, p38, and c-Jun N-terminal kinase (JNK). The activation of NF-B, p38, JNK, and dsRNA-dependent protein kinase is required for dsRNA-mediated iNOS gene expression. However, the activation of PI3 kinase and GSK-3 inhibited iNOS gene induction, a process mediated by their inhibitory effects on NF-B and p38 activation. dsRNA-induced NO production caused neuronal cell death in cultured dorsal root ganglion. Finally, the introduction of dsRNA into the rat sciatic nerve induced iNOS gene expression and peripheral nerve demyelination in vivo. Taken together, these data suggest that viral RNA may induce inflammatory Schwann cell activation via TLR3 and peripheral nerve damage in the PNS.