IRAK-M deficiency promotes the development of type 1 diabetes in NOD mice

Diabetes. 2014 Aug;63(8):2761-75. doi: 10.2337/db13-1504. Epub 2014 Apr 2.

Abstract

Type 1 diabetes mellitus (T1DM) is an organ-specific autoimmune disease characterized by progressive destruction of insulin-secreting pancreatic β-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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Autoantibodies
  • CD4-Positive T-Lymphocytes
  • Cytokines / genetics
  • Cytokines / metabolism
  • Diabetes Mellitus, Type 1 / genetics
  • Diabetes Mellitus, Type 1 / immunology
  • Diabetes Mellitus, Type 1 / metabolism*
  • Gene Expression Regulation
  • Insulin / immunology
  • Interleukin-1 Receptor-Associated Kinases / genetics
  • Interleukin-1 Receptor-Associated Kinases / metabolism*
  • Lymphocyte Activation / physiology
  • Mice
  • Mice, Inbred NOD
  • Mice, Knockout
  • Mice, SCID
  • Mice, Transgenic

Substances

  • Autoantibodies
  • Cytokines
  • Insulin
  • Interleukin-1 Receptor-Associated Kinases
  • Irak3 protein, mouse