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

Tan, Q., Majewska-Szczepanik, M., Zhang, X., Szczepanik, M., Zhou, Z., Wong, Florence Susan ORCID: https://orcid.org/0000-0002-2812-8845 and Wen, L. 2014. IRAK-M deficiency promotes the development of type 1 diabetes in NOD mice. Diabetes 63 (8) , pp. 2761-2775. 10.2337/db13-1504

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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.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Medicine
Subjects:	R Medicine > R Medicine (General)
Publisher:	American Diabetes Association
ISSN:	0012-1797
Date of Acceptance:	27 March 2014
Last Modified:	01 Nov 2022 09:30
URI:	https://orca.cardiff.ac.uk/id/eprint/88155

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