期刊
DIABETES
卷 63, 期 8, 页码 2761-2775出版社
AMER DIABETES ASSOC
DOI: 10.2337/db13-1504
关键词
-
资金
- National Institutes of Health grants [1RC1DK08769, DK-088181, DK-07991]
- Diabetes Research Center grant [P30 (DK-06-014)]
- JDRF grant [47-2013-516]
Type 1 diabetes mellitus (T1DM) is an organ-specific autoimmune disease characterized by progressive destruction of insulin-secreting pancreatic beta-cells. Both T-cell-mediated adaptive responses as well as innate immune processes are involved in pathogenesis. Interleukin-1 receptor-associated kinase M (IRAK-M) can effectively inhibit the MyD88 downstream signals in Toll-like receptor pathways, while lack of IRAK-M is known to be associated with autoimmunity. Our study showed that IRAK-M-deficient (IRAK-M-/-) nonobese diabetic (NOD) mice displayed early onset and rapid progression of T1DM with impaired glucose tolerance, more severe insulitis, and increased serum anti-insulin autoantibodies. Mechanistic studies showed that the enhanced activation and antigen-presenting function of IRAK-M-/- antigen-presenting cells from IRAK-M-/- mice were responsible for the rapid progression of disease. Moreover, IRAK-M-/- dendritic cells induced enhanced activation of diabetogenic T cells in vitro and the rapid onset of T1DM in vivo in immunodeficient NOD mice when cotransferred with diabetogenic T cells. This study illustrates how the modulation of innate immune pathways through IRAK-M influences the development of autoimmune diabetes.
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