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

被引：1053

作者：

Masters, Seth L. ^{[1
,2
]}

Dunne, Aisling ^{[1
,3
]}

Subramanian, Shoba L. ^{[4
,5
]}

Hull, Rebecca L. ^{[4
,5
]}

Tannahill, Gillian M. ^{[2
]}

Sharp, Fiona A. ^{[6
]}

Becker, Christine ^{[2
]}

Franchi, Luigi ^{[7
,8
]}

Yoshihara, Eiji ^{[9
]}

Chen, Zhe ^{[9
]}

Mullooly, Niamh ^{[10
]}

Mielke, Lisa A. ^{[1
,3
]}

Harris, James ^{[1
,6
]}

Coll, Rebecca C. ^{[2
]}

Mills, Kingston H. G. ^{[1
,3
]}

Mok, K. Hun ^{[11
]}

Newsholme, Philip ^{[10
]}

Nunez, Gabriel ^{[7
,8
]}

Yodoi, Junji ^{[9
]}

Kahn, Steven E. ^{[4
,5
]}

Lavelle, Ed C. ^{[1
,6
]}

O'Neill, Luke A. J. ^{[1
,2
]}

机构：

[1] Trinity Coll Dublin, Sch Biochem & Immunol, Immunol Res Ctr, Dublin, Ireland

[2] Trinity Coll Dublin, Sch Biochem & Immunol, Inflammat Res Grp, Dublin, Ireland

[3] Trinity Coll Dublin, Sch Biochem & Immunol, Immune Regulat Res Grp, Dublin, Ireland

[4] VA Puget Sound Hlth Care Syst, Dept Med, Div Metab Endocrinol & Nutr, Seattle, WA USA

[5] Univ Washington, Seattle, WA 98195 USA

[6] Trinity Coll Dublin, Adjuvant Res Grp, Sch Biochem & Immunol, Dublin, Ireland

[7] Univ Michigan, Sch Med, Dept Pathol, Ann Arbor, MI 48109 USA

[8] Univ Michigan, Sch Med, Ctr Comprehens Canc, Ann Arbor, MI 48109 USA

[9] Kyoto Univ, Dept Biol Responses, Inst Virus Res, Kyoto 6068501, Japan

[10] Univ Coll Dublin, Sch Biomol & Biomed Sci, Conway Inst, Dublin 2, Ireland

[11] Trinity Coll Dublin, Sch Biochem & Immunol, Prot Folding & Biomol NMR Spect Grp, Dublin, Ireland

来源：

NATURE IMMUNOLOGY | 2010年 / 11卷 / 10期

基金：

英国医学研究理事会; 美国国家卫生研究院; 爱尔兰科学基金会;

关键词：

LOW-DENSITY-LIPOPROTEIN; BETA-CELL MASS; NALP3; INFLAMMASOME; TRANSGENIC MICE; MOUSE MODEL; AMYLIN; PROTEIN; CYTOKINE; FIBRILS; GLUCOSE;

D O I：

10.1038/ni.1935

中图分类号：

R392 [医学免疫学]; Q939.91 [免疫学];

学科分类号：

100102 ;

摘要：

Interleukin 1 beta (IL-1 beta) 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-1 beta. One therapy for type 2 diabetes, glyburide, suppressed IAPP-mediated IL-1 beta production in vitro. Processing of IL-1 beta 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-1 beta 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.

引用

页码：897 / U1501

页数：9

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