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

Cite this

Masters, S. L., Dunne, A., Subramanian, S. L., Hull, R. L., Tannahill, G. M., Sharp, F. A., Becker, C., Franchi, L., Yoshihara, E., Chen, Z., Mullooly, N., Mielke, L. A., Harris, J., Coll, R. C., Mills, K. H. G., Mok, K. H., Newsholme, P., Nunez, G., Yodoi, J., ... O'Neill, L. A. J. (2010). Activation of the NLRP3 inflammasome by islet amyloid polypeptide provides a mechanism for enhanced IL-1beta in type 2 diabetes. Nature Immunology, 11(10), 897 - 904. https://doi.org/10.1038/ni.1935