title: Differential Activation of Innate Immune Pathways by Distinct Islet Amyloid Polypeptide (IAPP) Aggregates.
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 induced NLRP3-dependent IL-1β secretion by LPS-primed macrophages. Moreover, inhibition of TLR2 and depletion of islet macrophages prevented up-regulation of Il1b and Tnf expression in human IAPP-expressing transgenic mouse islets. These data suggest participation by both soluble and fibrillar aggregates in IAPP-induced islet inflammation. IAPP-induced activation of TLR2 and secretion of IL-1 may be important therapeutic targets to prevent amyloid-associated beta cell dysfunction.
authors.affiliation: From the Departments of Pathology & Laboratory Medicine and.
authors.forename: Clara
authors.initials: C
authors.lastname: Westwell-Roper
authors.affiliation: Surgery, Child & Family Research Institute, University of British Columbia, Vancouver, British Columbia V5Z 4H4, Canada.
authors.forename: Heather C
authors.initials: HC
authors.lastname: Denroche
authors.affiliation: Surgery, Child & Family Research Institute, University of British Columbia, Vancouver, British Columbia V5Z 4H4, Canada.
authors.forename: Jan A
authors.initials: JA
authors.lastname: Ehses
authors.affiliation: From the Departments of Pathology & Laboratory Medicine and Surgery, Child & Family Research Institute, University of British Columbia, Vancouver, British Columbia V5Z 4H4, Canada bverchere@cfri.ca.
authors.forename: C Bruce
authors.initials: CB
authors.lastname: Verchere
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000276:immunology; D057809:HEK293 Cells; D006801:Humans; D007113:Immunity, Innate; D050417:Insulin-Secreting Cells / Q000276:immunology* / Q000473:pathology; D053583:Interleukin-1beta / Q000235:genetics / Q000276:immunology; D058228:Islet Amyloid Polypeptide / Q000235:genetics / Q000276:immunology*; D008070:Lipopolysaccharides / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D066263:Protein Aggregation, Pathological / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D051193:Toll-Like Receptors / Q000235:genetics / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000276:immunology
chemical_list: D002352:Carrier Proteins; C508585:IL1B protein, human; C587672:IL1B protein, mouse; D053583:Interleukin-1beta; D058228:Islet Amyloid Polypeptide; D008070:Lipopolysaccharides; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C453881:NLRP3 protein, human; C492716:Nlrp3 protein, mouse; D051193:Toll-Like Receptors; D014409:Tumor Necrosis Factor-alpha
keywords: amyloid; diabetes; innate immunity; protein aggregation; toll-like receptor (TLR)