The Role Of Interleukin-1Receptor Associated Kinase-M(IRAK-M) In The Development Of Type1Diabetes In Non-obese Diabetic Mice

Abstract:Type1diabetes 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-1receptor associated kinase M (IRAK-M) can effectively inhibit the MyD88downstream 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 TIDM with impaired glucose tolerance, severer 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 TIDM in vivo in immunodeficient NOD mice when co-transferred with diabetogenicT cells. This study illustrates how modulation of innate immune pathways through IRAK-M influences the development of autoimmune diabetes.