title: Activation of the NLRP3 inflammasome by islet amyloid polypeptide provides a mechanism for enhanced IL-1β in type 2 diabetes.
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 identify previously unknown mechanisms in the pathogenesis of type 2 diabetes and treatment of pathology caused by IAPP.
authors.affiliation: Immunology Research Centre, School of Biochemistry and Immunology, Trinity College, Dublin, Ireland. smasters@tcd.ie
authors.forename: Seth L
authors.initials: SL
authors.lastname: Masters
authors.forename: Aisling
authors.initials: A
authors.lastname: Dunne
authors.forename: Shoba L
authors.initials: SL
authors.lastname: Subramanian
authors.forename: Rebecca L
authors.initials: RL
authors.lastname: Hull
authors.forename: Gillian M
authors.initials: GM
authors.lastname: Tannahill
authors.forename: Fiona A
authors.initials: FA
authors.lastname: Sharp
authors.forename: Christine
authors.initials: C
authors.lastname: Becker
authors.forename: Luigi
authors.initials: L
authors.lastname: Franchi
authors.forename: Eiji
authors.initials: E
authors.lastname: Yoshihara
authors.forename: Zhe
authors.initials: Z
authors.lastname: Chen
authors.forename: Niamh
authors.initials: N
authors.lastname: Mullooly
authors.forename: Lisa A
authors.initials: LA
authors.lastname: Mielke
authors.forename: James
authors.initials: J
authors.lastname: Harris
authors.forename: Rebecca C
authors.initials: RC
authors.lastname: Coll
authors.forename: Kingston H G
authors.initials: KH
authors.lastname: Mills
authors.forename: K Hun
authors.initials: KH
authors.lastname: Mok
authors.forename: Philip
authors.initials: P
authors.lastname: Newsholme
authors.forename: Gabriel
authors.initials: G
authors.lastname: Nuñez
authors.forename: Junji
authors.initials: J
authors.lastname: Yodoi
authors.forename: Steven E
authors.initials: SE
authors.lastname: Kahn
authors.forename: Ed C
authors.initials: EC
authors.lastname: Lavelle
authors.forename: Luke A J
authors.initials: LA
authors.lastname: O'Neill
mesh_terms: D000682:Amyloid / Q000378:metabolism*; D000818:Animals; D002352:Carrier Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000276:immunology* / Q000378:metabolism; D005905:Glyburide / Q000494:pharmacology; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology; D053583:Interleukin-1beta / Q000378:metabolism*; D058228:Islet Amyloid Polypeptide; D007515:Islets of Langerhans / Q000378:metabolism; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D051381:Rats; D018160:Receptors, Cytoplasmic and Nuclear / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
chemical_list: D000682:Amyloid; D002352:Carrier Proteins; D007004:Hypoglycemic Agents; D053583:Interleukin-1beta; D058228:Islet Amyloid Polypeptide; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C453881:NLRP3 protein, human; C573346:Nlrp3 protein, rat; D018160:Receptors, Cytoplasmic and Nuclear; D005905:Glyburide