Differential Activation of Innate Immune Pathways by Distinct Islet Amyloid Polypeptide (IAPP) Aggregates.

The Journal of Biological Chemistry
Clara Westwell-RoperC Bruce Verchere

Abstract

Aggregation of islet amyloid polypeptide (IAPP) contributes to beta cell dysfunction in type 2 diabetes and islet transplantation. Like other amyloidogenic peptides, human IAPP induces macrophage IL-1β secretion by stimulating both the synthesis and processing of proIL-1β, a pro-inflammatory cytokine that (when chronically elevated) impairs beta cell insulin secretion. We sought to determine the specific mechanism of IAPP-induced proIL-1β synthesis. Soluble IAPP species produced early during IAPP aggregation provided a Toll-like-receptor-2- (TLR2-) dependent stimulus for NF-κB activation in HEK 293 cells and bone marrow-derived macrophages (BMDMs). Non-amyloidogenic rodent IAPP and thioflavin-T-positive fibrillar amyloid produced by human IAPP aggregation failed to activate TLR2. Blockade of TLR6 but not TLR1 prevented hIAPP-induced TLR2 activation, consistent with stimulation of a TLR2/6 heterodimer. TLR2 and its downstream adaptor protein MyD88 were required for IAPP-induced cytokine production by BMDMs, a process that is partially dependent on autoinduction by IL-1. BMDMs treated with soluble but not fibrillar IAPP provided a TLR2-dependent priming stimulus for ATP-induced IL-1β secretion, whereas late IAPP aggregates induce...Continue Reading

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Citations

Jan 23, 2017·Trends in Molecular Medicine·Meghana N PatelSeth L Masters
Jan 31, 2018·Journal of Molecular Endocrinology·Heather C Denroche, C Bruce Verchere
Dec 15, 2019·Nature Reviews. Endocrinology·Wei YingJerrold M Olefsky
Apr 3, 2020·Journal of Molecular Cell Biology·Jinglong Guo, Wenxian Fu
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Jan 30, 2020·Frontiers in Immunology·Yan-Mei HuangHai-Lu Zhao
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May 28, 2021·Immunology·Jean Gabriel de SouzaOlga Celia Martinez Ibañez
Oct 13, 2021·Journal of Cellular Physiology·Carine MarmentiniMirian A Kurauti

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