Double-stranded RNA induces pancreatic beta cell apoptosis by activation of the TLR3 and IRF-3 pathways

Abstract

Objective: Viral infections contribute to the pathogenesis of type 1 diabetes. Viruses, or viral products such as double-stranded RNA (dsRNA), affect pancreatic beta cell survival and trigger autoimmunity by unknown mechanisms. We presently investigated the mediators and downstream effectors of dsRNA-induced beta cell death.

Research Design and Methods: Primary rat beta cells and islet cells from wild type, Toll-like receptor 3 (TLR3), type I interferon receptor (IFNAR1) or interferon regulatory factor 3 (IRF-3) knockout mice were exposed to external dsRNA (polyinosinic polycytidylic acid; PICex) or were transfected with dsRNA (PICin).

Results: TLR3 signaling mediated PICex-induced NF-κB and IRF-3 activation and beta cell apoptosis. PICin activated NF-κB and IRF-3 in a TLR3-independent manner, induced eIF2α phosphorylation and triggered a massive production of IFN-β. This contributed to beta cell death as islet cells from IFNAR1^-/- or IRF-3^-/- mice were protected against PICin-induced apoptosis.

Conclusions: External and internal dsRNA trigger beta cell apoptosis via respectively the TLR3 pathway or IRF-3 signaling. Execution of PICin-mediated apoptosis depends on autocrine effects of type I IFNs.