Journal article

Activation of the NLRP3 inflammasome by islet amyloid polypeptide provides a mechanism for enhanced IL-1 beta 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 HG Mills, K Hun Mok, Philip Newsholme, Gabriel Nunez, Junji Yodoi, Steven E Kahn Show all

Nature Immunology | NATURE PUBLISHING GROUP | Published : 2010

Abstract

Interleukin 1β (IL-1β) 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-1β. One therapy for type 2 diabetes, glyburide, suppressed IAPP-mediated IL-1β production in vitro. Processing of IL-1β 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-1β in pancreatic islets, which localized together with amyloid and macrophages. Our findings id..

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University of Melbourne Researchers

Grants

Awarded by National Health and Medical Research Council


Awarded by US National Institutes of Health


Awarded by NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES


Awarded by NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES


Funding Acknowledgements

We thank A. Mori for assistance with Nlrp3<SUP>-/-</SUP> mice; J. Tschopp (University of Lausanne) for Nlrp3<SUP>-/-</SUP> mice; and E. Latz (University of Bonn) for YFP-ASC BMDMs. Supported by the National Health and Medical Research Council (516783 to S.L.M.), Science Foundation Ireland (for work at Trinity College Dublin), the United States Department of Veterans Affairs (for work at the VA Puget Sound Health Care System), the US National Institutes of Health (DK-75998 to S.E.K. for work at VA Puget Sound Health Care System, and AI063331 for work at the University of Michigan) and the Crohn's and Colitis Foundation (L.F.).