Activation of the Nlrp3 inflammasome by islet amyloid polypeptide provides a mechanism for enhanced IL-1β in type 2 diabetes

By S. Masters, A. Dunne, S. Subramanian, R. Hull, G. Tannahill, F. Sharp, Christine E. Becker, L. Franchi, E. Yoshihara, Zhe Chen and 12 more. Nature Immunology, 2010

1,300 citations recorded by the source corpus.

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.

Subfields: Genetics, Molecular Biology, Surgery

View Paper: https://www.semanticscholar.org/paper/60d64126a9a9f0cb137ba85804a3b2ccf0c59e7a

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Genetics

1. Rongbin Zhou
2. J. Tschopp
3. M. Lamkanfi
4. V. Dixit

In Molecular Biology

1. J. Tschopp
2. M. Lamkanfi
3. V. Dixit
4. E. Latz
5. Katherine A. Fitzgerald
6. Yuan He
7. Rongbin Zhou
8. Greta Guarda

In Surgery

1. J. Tschopp
2. M. Lamkanfi
3. K. Moore
4. V. Dixit

Citations in the corpus

• Inflammation as a link between obesity, metabolic syndrome and type 2 diabetes. (2014, background): “Moreover, islet amyloid polypeptide (IAPP), a protein that forms amyloid deposits in the pancreas, seems to contribute to IL-1b production in islets through activation of the NLRP3 inflammasome [54].”
• CD36 coordinates NLRP3 inflammasome activation by facilitating the intracellular nucleation from soluble to particulate ligands in sterile inflammation (2013, background): “In the AD brain and diabetic pancreas, amyloid plaques arise from the aggregation of pre-fibrillar amyloidogenic peptides such as the Aβ(1-42) peptide17, 18, 19 or IAPP20, 21, 22, which oligomerize and give rise to higher order structures, including fibrils.”
• NLRP3 Inflammasome and the IL-1 Pathway in Atherosclerosis. (2018, background): “It was shown that the pancreatic islet amyloid polypeptide, which is co-secreted with insulin, forms aggregates, which induce NLRP3dependent IL-1β secretion as well as NLRP3-dependent cell death of insulin-producing β-cells.(135,136) Moreover, saturated fatty acids were also shown to activate NLRP3 ”
• Omega-3 fatty acids prevent inflammation and metabolic disorder through inhibition of NLRP3 inflammasome activation. (2013, background): “As we and others have shown that the NLRP3 inflammasome is implicated in the development of insulin resistance in T2D (Masters et al., 2010; Vandanmagsar et al., 2011; Wen et al., 2011; Zhou et al., 2010), we investigated whetheru-3 FAs can improve insulin sensitivity via inhibition of inflammasome ”
• The inflammasome: an integrated view (2011, result): “However, other reports were unable to reproduce some of these findings (115), so it remains to be determined in what cell types and under what circumstances TXNIP contributes to inflammasome activation.”
• Islet amyloid polypeptide, islet amyloid, and diabetes mellitus. (2011, background): “An interesting recent finding is that aggregated IAPP can activate the inflammasome to produce processed interleukin-1 , which may cause -cell death (237).”