The location of sensing determines the pancreatic β-cell response to the viral mimetic dsRNA

• Published in: The Journal of biological chemistry 2020-02, Vol.295 (8), p.2385-2397
• Main Authors: Shaheen, Zachary R., Stafford, Joshua D., Voss, Michael G., Oleson, Bryndon J., Stancill, Jennifer S., Corbett, John A.
• Format: Article
• Language: English
• Subjects: Animals; Apoptosis - drug effects; autoimmune diabetes; beta cell; Caspases - metabolism; Cell Survival - drug effects; cytokine; diabetes; DNA Damage; dsRNA; dsRNA sensors; Enzyme Activation - drug effects; Gene Expression Regulation - drug effects; IFN response; IL-1; Immunology; inducible nitric oxide synthase; Inflammation - pathology; innate immunity; Insulin-Secreting Cells - virology; interferon; Interferon Type I - metabolism; Male; Nitric Oxide Synthase Type II - metabolism; pathogen-associated molecular pattern (PAMP); picornavirus; Poly I-C - pharmacology; poly(I:C); Rats, Sprague-Dawley; RNA, Double-Stranded - metabolism; RNA, Messenger - genetics; RNA, Messenger - metabolism; Signal Transduction - drug effects; Toll-Like Receptor 3 - metabolism; type I interferon
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.RA119.010267

Viral infection is an environmental trigger that has been suggested to initiate pancreatic β-cell damage, leading to the development of autoimmune diabetes. Viruses potently activate the immune system and can damage β cells by either directly infecting them or stimulating the production of secondary effector molecules (such as proinflammatory cytokines) during bystander activation. However, how and where β cells recognize viruses is unclear, and the antiviral responses that are initiated following virus recognition are incompletely understood. In this study, we show that the β-cell response to dsRNA, a viral replication intermediate known to activate antiviral responses, is determined by the cellular location of sensing (intracellular versus extracellular) and differs from the cellular response to cytokine treatment. Using biochemical and immunological methods, we show that β cells selectively respond to intracellular dsRNA by expressing type I interferons (IFNs) and inducing apoptosis, but that they do not respond to extracellular dsRNA. These responses differ from the activities of cytokines on β cells, which are mediated by inducible nitric oxide synthase expression and β-cell production of nitric oxide. These findings provide evidence that the antiviral activities of type I IFN production and apoptosis are elicited in β cells via the recognition of intracellular viral replication intermediates and that β cells lack the capacity to respond to extracellular viral intermediates known to activate innate immune responses.