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

¹Laboratory of Experimental Medicine, Université Libre de Bruxelles, Brussels, Belgium
²Centre d'Immunologie de Marseille-Luminy, CNRS-INSERM- Université de la Mediterranée, Marseille, France
³Institute of Medical Immunology, Université Libre de Bruxelles, Charleroi, Belgium
⁴Laboratory of Experimental Medicine and Endocrinology (LEGENDO), UZ Gasthuisberg O&N, Katholieke Universiteit Leuven, Leuven, Belgium
⁵Department for Molecular Biomedical Research, VIB - Ghent University, Ghent, Belgium

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-B and IRF-3 activation and beta cell apoptosis. PICin activated NF-B and IRF-3 in a TLR3-independent manner, induced eIF2 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.

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