MDA5-dependent responses contribute to autoimmune diabetes progression and hindrance

Abstract

Type 1 diabetes (T1D) is an autoimmune disease resulting in pancreatic β-cell destruction. Coxsackievirus B3 (CVB3) infection and melanoma differentiation-associated protein 5 (MDA5)-dependent antiviral responses are linked with T1D development. Mutations within IFIH1, encoding for MDA5, are correlated with T1D susceptibility, but how these mutations contribute to T1D remains unclear. Utilizing non-obese diabetic (NOD) mice lacking Ifih1 expression (KO) or containing an in-frame deletion within the ATPase site of the helicase 1 domain of MDA5 (ΔHel1), we tested the hypothesis that partial or complete loss-of-function mutations in MDA5 would delay T1D by impairing proinflammatory pancreatic macrophage and T cell responses. Spontaneous T1D developed in female NOD and KO mice similarly, but was significantly delayed in ΔHel1 mice that may be partly due to a concomitant increase in myeloidderived suppressor cells. Interestingly, KO male mice had increased spontaneous T1D compared to NOD mice. While NOD and KO mice developed CVB3-accelerated T1D, ΔHel1 mice were protected partly due to decreased type I interferons, pancreatic-infiltrating TNF + macrophages, IFNγ + CD4 + T cells, and perforin + CD8 + T cells. Furthermore, ΔHel1 MDA5 protein had reduced ATP hydrolysis compared to wild-type MDA5. Our results suggest that dampened MDA5 function delays T1D, yet loss of MDA5 promotes T1D.

The IFIH1-A946T risk variant promotes diabetes in a sex-dependent manner

“…Interestingly, a recent study showed that the complete absence of Ifih1 ( KO ) in NOD mice accelerated T1D in males, which was postulated to occur due to an inability of Ifih1 KO mice to produce sufficient myeloid-derived suppressor cells ( 19 ). In contrast, female NOD Ifih1 KO mice developed disease similarly compared to NOD mice ( 19 ).…”

“…Interestingly, a recent study showed that the complete absence of Ifih1 ( KO ) in NOD mice accelerated T1D in males, which was postulated to occur due to an inability of Ifih1 KO mice to produce sufficient myeloid-derived suppressor cells ( 19 ). In contrast, female NOD Ifih1 KO mice developed disease similarly compared to NOD mice ( 19 ). Further, both male and female NOD Ifih1 mice with an in-frame deletion in the HEL1 domain of IFIH1 (NOD.ΔHel1) exhibited delayed disease onset which was a result of decreased IFIH1-mediated ATP hydrolysis, IFN I production, and pancreatic immune cell infiltration by macrophages, CD4 + and CD8 + T cells ( 19 ).…”

“…Decreased expression of IFIH1 was found to significantly decrease diabetes incidence ( 17 ) in NOD/ShiLtJ (NOD) mice, a spontaneous mouse model for T1D ( 18 ). NOD mice with an in-frame deletion in the Ifih1 helicase domain exhibited decreased insulitis, IFN I production, and delayed onset of T1D ( 19 ). In contrast, the complete absence of Ifih1 ( KO ) accelerated T1D in male mice, which was postulated to occur due to an inability of Ifih1 KO mice to produce sufficient myeloid-derived suppressor cells ( 19 ).…”

“…Altogether, these findings highlight functional roles of IFIH1 in T1D pathogenesis. A recent study suggests that IFIH1 plays a role in immune cell compartments during T1D pathogenesis, particularly in the macrophages and T cells ( 19 ). However, how IFIH1 R may alter the immune system contributing to T1D pathogenesis remains unresolved.…”

Stress-induced endogenous-dsRNAs drive beta-cells to IFN-I state

“…Within discordant type 1 diabetic-monozygotic twins, hypervariable DNA-methylation of immune effector cells was found to be a defining feature in the diabetic twin, suggesting a connection between epigenetic dysregulation and diabetes [20]. Individuals with type 1 diabetes have been observed to have increased IFN-I signaling (as gauged by IFNB1 expression), suggesting activation of RLRs [9, 13, 21]. Additionally, landmark GWAS studies on type 1 diabetic individuals have implicated one such RLR, MDA5 / IFIH1, an antiviral dsRNA-surveillance protein for IFN-I signaling, as a top risk locus for disease onset [11, 22].…”