Role of MDA5 responses on islet-resident macrophages in Type 1 diabetes

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Project Summary Type 1 diabetes (T1D) is an autoimmune disease resulting in pancreatic β-cell destruction due to the generation of proinflammatory cytokines/chemokines generated by T cells, macrophages, and other immune cells. Recent evidence has revealed that coxsackievirus group B (CVB) infection and an increase in innate viral sensor melanoma differentiation- associated protein 5 (MDA5) responses are correlated to T1D development in humans. In mice, CVB infection accelerates T1D development in part due to MDA5 upregulation. To study the role of MDA5 in T1D, we have generated a novel NOD mouse model called NOD.Ifih1ΔHel1. NOD.Ifih1ΔHel1 mice contain a mutation in the helicase 1 domain of Ifih1, the gene encoding for MDA5. Mice expressing the Ifih1ΔHel1 mutation exhibit a delay in T1D development, due to reduced proinflammatory macrophage and T cell responses within the pancreata. However, it remains unclear how MDA5 biochemical function alters innate and adaptive immune cells to regulate T1D onset. I will determine how MDA5 biochemical function affects islet-resident macrophages (IRMs) responses to either promote or dampen T1D development. I will determine if the Ifih1ΔHel1 mutation on IRMs affects innate pathogen sensing and antigen presentation to delay T1D. To enhance the understanding of how MDA5 can regulate autoimmunity, I will examine the function of WT and Ifih1ΔHel1 MDA5 ATPase activity and dsRNA binding. I hypothesize that reduced MDA5 ATPase activity can dampen IRM responsiveness within the islets, thereby reducing inflammation, activation of autoreactive T cells, and subsequently, delaying T1D onset. To test this hypothesis, the following independent aims will be defined: (i) Determine if the Ifih1ΔHel1 mutation impairs macrophage viral sensing and antigen presentation. (ii) Determine if the Ifih1ΔHel1 mutation results in reduced ATPase activity and dsRNA binding of MDA5. The insights gained from these studies will increase our understanding of the role of MDA5 on IRMs to drive autoimmune T1D and pancreatic β-cells destruction.