| First Author | Blum SI | Year | 2023 |
| Journal | JCI Insight | Volume | 8 |
| Issue | 2 | PubMed ID | 36512407 |
| Mgi Jnum | J:339647 | Mgi Id | MGI:7441405 |
| Doi | 10.1172/jci.insight.157929 | Citation | Blum SI, et al. (2023) MDA5-dependent responses contribute to autoimmune diabetes progression and hindrance. JCI Insight 8(2) |
| abstractText | Type 1 diabetes (T1D) is an autoimmune disease resulting in pancreatic beta cell destruction. Coxsackievirus B3 (CVB3) infection and melanoma differentiation-associated protein 5-dependent (MDA5-dependent) antiviral responses are linked with T1D development. Mutations within IFIH1, coding for MDA5, are correlated with T1D susceptibility, but how these mutations contribute to T1D remains unclear. Utilizing nonobese diabetic (NOD) mice lacking Ifih1 expression (KO) or containing an in-frame deletion within the ATPase site of the helicase 1 domain of MDA5 (DeltaHel1), 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 DeltaHel1 mice, which may be partly due to a concomitant increase in myeloid-derived suppressor cells. Interestingly, KO male mice had increased spontaneous T1D compared with NOD mice. Whereas NOD and KO mice developed CVB3-accelerated T1D, DeltaHel1 mice were protected partly due to decreased type I IFNs, pancreatic infiltrating TNF+ macrophages, IFN-gamma+CD4+ T cells, and perforin+CD8+ T cells. Furthermore, DeltaHel1 MDA5 protein had reduced ATP hydrolysis compared with wild-type MDA5. Our results suggest that dampened MDA5 function delays T1D, yet loss of MDA5 promotes T1D. |
