IRAK-M Deficiency Promotes the Development of Type 1 Diabetes in NOD Mice
- Qiyuan Tan1,2,
- Monika Majewska-Szczepanik2,3,
- Xiaojun Zhang2,
- Marian Szczepanik2,3,
- Zhiguang Zhou1,
- F. Susan Wong4 and
- Li Wen2⇑
- 1Institution of Metabolism and Endocrinology, the Second Xiangya Hospital, Central South University, Changsha, People’s Republic of China
- 2Section of Endocrinology, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT
- 3Department of Medical Biology, Jagiellonian University Medical College, Krakow, Poland
- 4Institute of Molecular and Experimental Medicine, Cardiff School of Medicine, Cardiff University, Cardiff, U.K.
- Corresponding author: Li Wen, .
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.
This article contains Supplementary Data online at http://diabetes.diabetesjournals.org/lookup/suppl/doi:10.2337/db13-1504/-/DC1.
- Received October 1, 2013.
- Accepted March 27, 2014.
- © 2014 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.