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

• Published in: Nature immunology Vol. 11; no. 10; pp. 897 - 904
• Main Authors: Mullooly, Niamh, Mills, Kingston H G, O'Neill, Luke A J, Kahn, Steven E, Mok, K Hun, Chen, Zhe, Tannahill, Gillian M, Dunne, Aisling, Becker, Christine, Sharp, Fiona A, Lavelle, Ed C, Yoshihara, Eiji, Mielke, Lisa A, Franchi, Luigi, Yodoi, Junji, Subramanian, Shoba L, Harris, James, Coll, Rebecca C, Newsholme, Philip, Masters, Seth L, Hull, Rebecca L, Nuñez, Gabriel
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.10.2010; Nature Publishing Group
• Subjects: 631/250/127/1213; 631/250/256/2177; 631/80/304; 692/699/2743/137/773; Amyloid - metabolism; Animals; Biomedical and Life Sciences; Biomedicine; Carrier Proteins - antagonists & inhibitors; Carrier Proteins - genetics; Carrier Proteins - metabolism; Cells, Cultured; Dendritic Cells - immunology; Dendritic Cells - metabolism; Diabetes Mellitus, Type 2 - immunology; Diabetes Mellitus, Type 2 - metabolism; Glyburide - pharmacology; Glycoproteins; Humans; Hypoglycemic Agents - pharmacology; Immunology; Infectious Diseases; Interleukin-1; Interleukin-1beta - metabolism; Islet Amyloid Polypeptide; Islets of Langerhans - metabolism; Macrophages - immunology; Macrophages - metabolism; Mice; Mice, Inbred C57BL; Mice, Transgenic; NLR Family, Pyrin Domain-Containing 3 Protein; Physiological aspects; Rats; Receptors, Cytoplasmic and Nuclear - antagonists & inhibitors; Receptors, Cytoplasmic and Nuclear - genetics; Receptors, Cytoplasmic and Nuclear - metabolism; Risk factors; Type 2 diabetes; United States; Innate immunity; Inflammation; Cytokines; Macrophages
• ISSN: 1529-2908; 1529-2916; 1529-2916
• DOI: 10.1038/ni.1935

Pancreatic islets in type 2 diabetes show characteristic deposition of the amyloid polypeptide IAPP. O'Neill and colleagues show that IAPP induces IL-1β production via the NLRP3 inflammasome, which leads to beta-cell destruction. 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 identify previously unknown mechanisms in the pathogenesis of type 2 diabetes and treatment of pathology caused by IAPP.