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; Ed C Lavelle; Luke A J O'Neill

doi:10.1038/ni.1935

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

Centre for Inflammatory Disease Monash Health

Research output: Contribution to journal › Article › Research › peer-review

1143 Citations (Scopus)

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 language	English
Pages (from-to)	897 - 904
Number of pages	8
Journal	Nature Immunology
Volume	11
Issue number	10
DOIs	https://doi.org/10.1038/ni.1935
Publication status	Published - 2010

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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

@article{bdf67dd398894bb69b43ac2f0466ad44,

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",

volume = "11",

pages = "897 -- 904",

journal = "Nature Immunology",

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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

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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

UR - https://www.scopus.com/pages/publications/77956958947

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DO - 10.1038/ni.1935

M3 - Article

SN - 1529-2908

VL - 11

SP - 897

EP - 904

JO - Nature Immunology

JF - Nature Immunology

IS - 10

ER -

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

Abstract

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