Introduction: Enterovirus infection has long been suspected as a possible trigger for type 1 diabetes. Upon infection, viral double-stranded RNA (dsRNA) is recognized by membrane and cytosolic... Show moreIntroduction: Enterovirus infection has long been suspected as a possible trigger for type 1 diabetes. Upon infection, viral double-stranded RNA (dsRNA) is recognized by membrane and cytosolic sensors that orchestrate type I interferon signaling and the recruitment of innate immune cells to the pancreatic islets. In this context, adenosine deaminase acting on RNA 1 (ADAR1) editing plays an important role in dampening the immune response by inducing adenosine mispairing, destabilizing the RNA duplexes and thus preventing excessive immune activation.Methods: Using high-throughput RNA sequencing data from human islets and EndoC-beta H1 cells exposed to IFN alpha or IFN gamma/IL1 beta, we evaluated the role of ADAR1 in human pancreatic beta cells and determined the impact of the type 1 diabetes pathophysiological environment on ADAR1-dependent RNA editing.Results: We show that both IFN alpha and IFN gamma/IL1 beta stimulation promote ADAR1 expression and increase the A-to-I RNA editing of Alu-Containing mRNAs in EndoC-beta H1 cells as well as in primary human islets.Discussion: We demonstrate that ADAR1 overexpression inhibits type I interferon response signaling, while ADAR1 silencing potentiates IFN alpha effects. In addition, ADAR1 overexpression triggers the generation of alternatively spliced mRNAs, highlighting a novel role for ADAR1 as a regulator of the beta cell transcriptome under inflammatory conditions. Show less
IFNa is a key regulator of the dialogue between pancreatic 0 cells and the immune system in early type 1 diabetes (T1D). IFNa up-regulates HLA class I expression in human 0 cells, fostering... Show moreIFNa is a key regulator of the dialogue between pancreatic 0 cells and the immune system in early type 1 diabetes (T1D). IFNa up-regulates HLA class I expression in human 0 cells, fostering autoantigen presentation to the immune system. We observed by bulk and single-cell RNA sequencing that exposure of human induced pluripotentderived islet-like cells to IFNa induces expression of HLA class I and of other genes involved in antigen presentation, including the transcriptional activator NLRC5. We next evaluated the global role of NLRC5 in human insulinproducing EndoC-0H1 and human islet cells by RNA sequencing and targeted gene/protein determination. NLRC5 regulates expression of HLA class I, antigen presentation-related genes, and chemokines. NLRC5 also mediates the effects of IFNa on alternative splicing, a generator of 0 cell neoantigens, suggesting that it is a central player of the effects of IFNa on 0 cells that contribute to trigger and amplify autoimmunity in T1D. Show less
