Activation of the NLRP3 inflammasome by islet amyloid polypeptide provides a mechanism for enhanced IL-1beta in type 2 diabetes

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

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Abstract

Interleukin 1beta (IL-1beta) is an important inflammatory mediator of type 2 diabetes. Here we show that oligomers of islet amyloid polypeptide (IAPP), a protein that forms amyloid deposits in the pancreas during type 2 diabetes, triggered the NLRP3 inflammasome and generated mature IL-1beta. One therapy for type 2 diabetes, glyburide, suppressed IAPP-mediated IL-1beta production in vitro. Processing of IL-1beta initiated by IAPP first required priming, a process that involved glucose metabolism and was facilitated by minimally oxidized low-density lipoprotein. Finally, mice transgenic for human IAPP had more IL-1beta in pancreatic islets, which localized together with amyloid and macrophages. Our findings identify previously unknown mechanisms in the pathogenesis of type 2 diabetes and treatment of pathology caused by IAPP.
Original languageEnglish
Pages (from-to)897 - 904
Number of pages8
JournalNature Immunology
Volume11
Issue number10
DOIs
Publication statusPublished - 2010

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