IRAK-M deficiency promotes the development of T1DM in NOD mice

  1. Li Wen2,*
  1. 1Institution of Metabolism and Endocrinology, the Second Xiangya Hospital, Central South University, Changsha, China,
  2. 2Section of Endocrinology, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT, USA,
  3. 3Dept of Med Biology, UJ Med College, Krakow, Poland,
  4. 4Institute of Molecular and Experimental Medicine, Cardiff School of Medicine, Cardiff University, U.K.
  1. *Corresponding author: Li Wen Email: li.wen{at}yale.edu

Abstract

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 TLR pathways, while lack of IRAK-M is known to be associated with autoimmunity. Our study showed that IRAK-M deficient (IRAK-M-/-) non obese diabetic (NOD) mice displayed early onset and rapid progression of T1DM with impaired glucose tolerance, more severe insulitis and increased serum anti-insulin auto-antibodies. Mechanistic studies showed that enhanced activation and antigen presenting function of IRAK-M deficient antigen presenting cells (APCs) from IRAK-M-/- mice were responsible for rapid progression of disease. Moreover, IRAK-M-/- dendritic cells (DCs) induced enhanced activation of diabetogenic T cells in vitro and rapid onset of T1DM in vivo in immunodeficient NOD mice when co-transferred with diabetogenic T cells. This study illustrates how modulation of innate immune pathways through IRAK-M influences the development of autoimmune diabetes.

  • Received October 1, 2013.
  • Accepted March 27, 2014.

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  1. Diabetes
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