The location of sensing determines the pancreatic β-cell response to the viral mimetic dsRNA. J Biol Chem 2020 Feb 21;295(8):2385-2397
Date
01/10/2020Pubmed ID
31915247Pubmed Central ID
PMC7039570DOI
10.1074/jbc.RA119.010267Scopus ID
2-s2.0-85079888996 (requires institutional sign-in at Scopus site) 4 CitationsAbstract
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.
Author List
Shaheen ZR, Stafford JD, Voss MG, Oleson BJ, Stancill JS, Corbett JAAuthors
John A. Corbett PhD Chair, Professor in the Biochemistry department at Medical College of WisconsinMichael G. Voss MD Assistant Professor in the Medicine department at Medical College of Wisconsin
MESH terms used to index this publication - Major topics in bold
AnimalsApoptosis
Caspases
Cell Survival
DNA Damage
Enzyme Activation
Gene Expression Regulation
Inflammation
Insulin-Secreting Cells
Interferon Type I
Male
Nitric Oxide Synthase Type II
Poly I-C
RNA, Double-Stranded
RNA, Messenger
Rats, Sprague-Dawley
Signal Transduction
Toll-Like Receptor 3
