RNA-editing, a fundamental cellular process, involves the deamination of adenosines in RNA to inosines by adenosine deaminases acting on RNA (ADAR). In recent years, this process has emerged as crucial for dismantling endogenous dsRNA structures produced by retroelements inserted in an inverted orientation in expressed genes. When RNA editing is impaired, endogenous dsRNA accumulates and is sensed by IFIH1 which activates an anti-viral gene expression program that may lead to pathogenic inflammation. RNA editing has been studied in several organs and cancer, yet little is known about its importance in pancreatic beta-cell biology. Furthermore, since islet inflammation is a feature of type 1 diabetes (T1D) and likely type 2 diabetes, and since GWAS revealed protective variants of IFIH1 on T1D risk, alterations in deamination might contribute to islet inflammation in diabetes.
We hypothesize that disrupted RNA editing in beta-cells triggers an interferon response, causing islet inflammation and potentially contributing to autoimmune destruction of beta-cells.
To test this hypothesis, we deleted the Adar1 gene in beta-cells of adult mice. We found that reduced editing results in the induction of interferon-stimulated genes, triggering a massive immune response involving the recruitment of both innate and adaptive immune cells. The recruitment of immune cells led to a cell-autonomous disruption of the -cell expression program (only in Adar1-deficient cells).
Around 30% of mutant mice develop diabetes and in diabetic mice, Adar-deficient beta-cells are eventually eliminated. Ongoing experiments assess the role of adaptive immunity in RNA editing-related beta-cell dysfunction and destruction.
Despite the extensive immune response in and around islets, α-cells remain unscathed, reminiscent of α-cell persistence in T1D. To study the basis for α-cell sparing, we disrupted ADAR1 specifically in α-cells of young mice. Strikingly, in contrast to the phenotype of β-cell ADAR1 disruption, neither an immune response nor a metabolic phenotype was observed. Ongoing experiments are aimed at understanding the unique resistance of α-cells to ADAR1 deficiency.
Our findings reveal the essential anti-inflammatory effect of RNA-editing in beta cells. Moreover, we present a new model for the interferon response and the presence of innate immune cells in pancreatic islets that characterize the early stages of T1D. Finally, this model will be useful for the study of the beta-immune cell interplay in T1D pathogenesis. 

Adar-mediated RNA editing in pancreatic beta-cells prevents aberrant innate immune activation and diabetes

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