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 Kahn & 2 others Ed C Lavelle, Luke A J O'Neill

Research output: Contribution to journalArticleResearchpeer-review

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., ... 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
Masters, Seth L ; Dunne, Aisling ; Subramanian, Shoba L ; Hull, Rebecca L ; Tannahill, Gillian M ; Sharp, Fiona A ; Becker, Christine ; Franchi, Luigi ; Yoshihara, Eiji ; Chen, Zhe ; Mullooly, Niamh ; Mielke, Lisa A ; Harris, James ; Coll, Rebecca C ; Mills, Kingston H G ; Mok, Kenneth Hun ; Newsholme, Philip ; Nunez, Gabriel ; Yodoi, Junji ; Kahn, Steven E ; Lavelle, Ed C ; O'Neill, Luke A J. / Activation of the NLRP3 inflammasome by islet amyloid polypeptide provides a mechanism for enhanced IL-1beta in type 2 diabetes. In: Nature Immunology. 2010 ; Vol. 11, No. 10. pp. 897 - 904.
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title = "Activation of the NLRP3 inflammasome by islet amyloid polypeptide provides a mechanism for enhanced IL-1beta in type 2 diabetes",
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.",
author = "Masters, {Seth L} and Aisling Dunne and Subramanian, {Shoba L} and Hull, {Rebecca L} and Tannahill, {Gillian M} and Sharp, {Fiona A} and Christine Becker and Luigi Franchi and Eiji Yoshihara and Zhe Chen and Niamh Mullooly and Mielke, {Lisa A} and James Harris and Coll, {Rebecca C} and Mills, {Kingston H G} and Mok, {Kenneth Hun} and Philip Newsholme and Gabriel Nunez and Junji Yodoi and Kahn, {Steven E} and Lavelle, {Ed C} and O'Neill, {Luke A J}",
year = "2010",
doi = "10.1038/ni.1935",
language = "English",
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Masters, SL, Dunne, A, Subramanian, SL, Hull, RL, Tannahill, GM, Sharp, FA, Becker, C, Franchi, L, Yoshihara, E, Chen, Z, Mullooly, N, Mielke, LA, Harris, J, Coll, RC, Mills, KHG, Mok, KH, Newsholme, P, Nunez, G, Yodoi, J, Kahn, SE, Lavelle, EC & O'Neill, LAJ 2010, 'Activation of the NLRP3 inflammasome by islet amyloid polypeptide provides a mechanism for enhanced IL-1beta in type 2 diabetes' Nature Immunology, vol. 11, no. 10, pp. 897 - 904. https://doi.org/10.1038/ni.1935

Activation of the NLRP3 inflammasome by islet amyloid polypeptide provides a mechanism for enhanced IL-1beta in type 2 diabetes. / Masters, Seth L; Dunne, Aisling; Subramanian, Shoba L; Hull, Rebecca L; Tannahill, Gillian M; Sharp, Fiona A; Becker, Christine; Franchi, Luigi; Yoshihara, Eiji; Chen, Zhe; Mullooly, Niamh; Mielke, Lisa A; Harris, James; Coll, Rebecca C; Mills, Kingston H G; Mok, Kenneth Hun; Newsholme, Philip; Nunez, Gabriel; Yodoi, Junji; Kahn, Steven E; Lavelle, Ed C; O'Neill, Luke A J.

In: Nature Immunology, Vol. 11, No. 10, 2010, p. 897 - 904.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Activation of the NLRP3 inflammasome by islet amyloid polypeptide provides a mechanism for enhanced IL-1beta in type 2 diabetes

AU - Masters, Seth L

AU - Dunne, Aisling

AU - Subramanian, Shoba L

AU - Hull, Rebecca L

AU - Tannahill, Gillian M

AU - Sharp, Fiona A

AU - Becker, Christine

AU - Franchi, Luigi

AU - Yoshihara, Eiji

AU - Chen, Zhe

AU - Mullooly, Niamh

AU - Mielke, Lisa A

AU - Harris, James

AU - Coll, Rebecca C

AU - Mills, Kingston H G

AU - Mok, Kenneth Hun

AU - Newsholme, Philip

AU - Nunez, Gabriel

AU - Yodoi, Junji

AU - Kahn, Steven E

AU - Lavelle, Ed C

AU - O'Neill, Luke A J

PY - 2010

Y1 - 2010

N2 - 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.

AB - 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.

UR - http://www.ncbi.nlm.nih.gov/pubmed/20835230

U2 - 10.1038/ni.1935

DO - 10.1038/ni.1935

M3 - Article

VL - 11

SP - 897

EP - 904

JO - Nature Immunology

JF - Nature Immunology

SN - 1529-2908

IS - 10

ER -