Activation of the Nlrp3 inflammasome by islet amyloid polypeptide provides a mechanism for enhanced IL-1β in type 2 diabetes

Seth L Masters (1) , Aisling Dunne (1) , Shoba L Subramanian (1) , Rebecca L Hull (1) , Gillian M Tannahill (1) , Fiona A Sharp (1) , Christine E Becker (1) , Luigi Franchi (1) , Eiji Yoshihara (1) , Zhe Chen (1) , Niamh Mullooly (1) , Lisa A Mielke (1) , James Harris (1) , Rebecca Clare Coll (1) , Kingston H.G. Mills (1) , K. Hun Mok (1) , Philip Newsholme (1) , Gabriel Nunez (1) , Junji Yodoi (1) , Steven E Kahn (1) , Ed C Lavelle (1) , Luke A. O'Neill (1)

1 School of Biochemistry and Immunology

IL-1β is an important inflammatory mediator of type 2 diabetes (T2D). Here we show that oligomers of islet amyloid polypeptide (IAPP), a protein that forms amyloid deposits in the pancreas during T2D, trigger the Nlrp3 inflammasome and generate mature interleukin (IL)-1β. A T2D therapy, glyburide, suppresses IAPP-mediated IL-1β production in vitro. Processing of IL-1β initiated by IAPP first requires priming, a process that involves glucose metabolism and can be facilitated by minimally oxidized low density lipoprotein. Finally, mice transgenic for human IAPP have increased IL-1β in pancreatic islets, which colocalizes with amyloid and macrophages. Our findings reveal novel mechanisms in the pathogenesis of T2D and treatment of pathology caused by IAPP.

Mots clés: Inflammation; Cytokines; Innate immunity; Macrophages

Seth L Masters, Aisling Dunne, Shoba L Subramanian, Rebecca L Hull, Gillian M Tannahill, et al.. Activation of the Nlrp3 inflammasome by islet amyloid polypeptide provides a mechanism for enhanced IL-1β in type 2 diabetes. Nature Immunology, 2010, 11 (10), pp.897. ⟨10.1038/ni.1935⟩. ⟨hal-00576089⟩