Activation of the NLRP3 inflammasome by islet amyloid polypeptide provides a mechanism for enhanced IL-1β 2 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; K. Hun Mok; Philip Newsholme; Gabriel Nuñez; 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-1β 2 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, K. Hun Mok, Philip Newsholme, Gabriel Nuñez, Junji Yodoi, Steven E. KahnEd C. Lavelle, Luke A.J. O'Neill

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Abstract

Interleukin 1β 2 (IL-1β 2) 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 2. One therapy for type 2 diabetes, glyburide, suppressed IAPP-mediated IL-1β 2 production in vitro. Processing of IL-1β 2 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 2 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 - 01 Oct 2010
Externally published	Yes

ASJC Scopus subject areas

Immunology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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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., Nuñez, G., Yodoi, J., ... O'Neill, L. A. J. (2010). Activation of the NLRP3 inflammasome by islet amyloid polypeptide provides a mechanism for enhanced IL-1β 2 in type 2 diabetes. Nature Immunology, 11(10), 897-904. https://doi.org/10.1038/ni.1935

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

abstract = "Interleukin 1β 2 (IL-1β 2) 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 2. One therapy for type 2 diabetes, glyburide, suppressed IAPP-mediated IL-1β 2 production in vitro. Processing of IL-1β 2 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 2 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, {K. Hun} and Philip Newsholme and Gabriel Nu{\~n}ez and Junji Yodoi and Kahn, {Steven E.} and Lavelle, {Ed C.} and O'Neill, {Luke A.J.}",

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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, Nuñez, 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-1β 2 in type 2 diabetes', Nature Immunology, vol. 11, no. 10, pp. 897-904. https://doi.org/10.1038/ni.1935

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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, K. Hun

AU - Newsholme, Philip

AU - Nuñez, Gabriel

AU - Yodoi, Junji

AU - Kahn, Steven E.

AU - Lavelle, Ed C.

AU - O'Neill, Luke A.J.

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

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

Abstract

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UN SDGs

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