MDA5-dependent responses contribute to autoimmune diabetes progression and hindrance. JCI Insight 2023 Jan 24;8(2)
Date
12/14/2022Pubmed ID
36512407Pubmed Central ID
PMC9977297DOI
10.1172/jci.insight.157929Scopus ID
2-s2.0-85147047458 (requires institutional sign-in at Scopus site) 3 CitationsAbstract
Type 1 diabetes (T1D) is an autoimmune disease resulting in pancreatic β 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 (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, 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, ΔHel1 mice were protected partly due to decreased type I IFNs, pancreatic infiltrating TNF+ macrophages, IFN-γ+CD4+ T cells, and perforin+CD8+ T cells. Furthermore, ΔHel1 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.
Author List
Blum SI, Taylor JP, Barra JM, Burg AR, Shang Q, Qiu S, Shechter O, Hayes AR, Green TJ, Geurts AM, Chen YG, Tse HMAuthors
Yi-Guang Chen PhD Professor in the Pediatrics department at Medical College of WisconsinAron Geurts PhD Professor in the Physiology department at Medical College of Wisconsin
MESH terms used to index this publication - Major topics in bold
AnimalsDiabetes Mellitus, Type 1
Female
Interferon-Induced Helicase, IFIH1
Macrophages
Male
Mice
Mice, Inbred NOD
Pancreas
