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.
Highlights
Mon pathological features of pancreatic islets from patients with type 2 diabetes
Human islet amyloid polypeptide (IAPP) Aggregation Intermediates Activate a TLR2/6 Heterodimer—To determine whether the initial signal for induction of proIL-1 synthesis by human IAPP is delivered by TLR activation, we screened a panel of human TLR-expressing HEK 293 cells co-transfected with an NF-B/
Recent work has demonstrated that IAPP activates caspase-1 and NLRP3 in cultured macrophages [8, 9] and islet macrophages [7], induces expression of Il1b and proIL-1 [7, 8, 26], and triggers secretion of mature IL-1 by bone marrow-derived macrophages [7]
Summary
Mon pathological features of pancreatic islets from patients with type 2 diabetes. Amyloid deposits are comprised primarily of islet amyloid polypeptide (IAPP),5 a 37-amino acid peptide that is co-secreted with insulin by beta cells. Dissolved hIAPP but not non-amyloidogenic rodent IAPP (rIAPP) or pre-aggregated fibrillar hIAPP triggered TLR2 signaling (Fig. 1D), an effect observed in HEK 293 cells expressing mouse TLR2 (Fig. 1E).
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