IL-1 Blockade Attenuates Islet Amyloid Polypeptide-Induced Proinflammatory Cytokine Release and Pancreatic Islet Graft Dysfunction

Abstract

Islets from patients with type 2 diabetes exhibit β cell dysfunction, amyloid deposition, macrophage infiltration, and increased expression of proinflammatory cytokines and chemokines. We sought to determine whether human islet amyloid polypeptide (hIAPP), the main component of islet amyloid, might contribute to islet inflammation by recruiting and activating macrophages. Early aggregates of hIAPP, but not nonamyloidogenic rodent islet amyloid polypeptide, caused release of CCL2 and CXCL1 by islets and induced secretion of TNF-α, IL-1α, IL-1β, CCL2, CCL3, CXCL1, CXCL2, and CXCL10 by C57BL/6 bone marrow-derived macrophages. hIAPP-induced TNF-α secretion was markedly diminished in MyD88-, but not TLR2- or TLR4-deficient macrophages, and in cells treated with the IL-1R antagonist (IL-1Ra) anakinra. To determine the significance of IL-1 signaling in hIAPP-induced pancreatic islet dysfunction, islets from wild-type or hIAPP-expressing transgenic mice were transplanted into diabetic NOD/SCID recipients implanted with mini-osmotic pumps containing IL-1Ra (50 mg/kg/d) or saline. IL-1Ra significantly improved the impairment in glucose tolerance observed in recipients of transgenic grafts 8 wk following transplantation. Islet grafts expressing hIAPP contained amyloid deposits in close association with F4/80-expressing macrophages. Transgenic grafts contained 50% more macrophages than wild-type grafts, an effect that was inhibited by IL-1Ra. Our results suggest that hIAPP-induced islet chemokine secretion promotes macrophage recruitment and that IL-1R/MyD88, but not TLR2 or TLR4 signaling is required for maximal macrophage responsiveness to prefibrillar hIAPP. These data raise the possibility that islet amyloid-induced inflammation contributes to β cell dysfunction in type 2 diabetes and islet transplantation.

Loss of prohormone convertase 2 promotes beta cell dysfunction in a rodent transplant model expressing human pro-islet amyloid polypeptide

“…These observations are in contrast with our previous in vitro findings [29]. Mature amyloid fibrils appear to be less deleterious to beta cells than prefibrillar species and improvements in glucose tolerance do not always correlate with reduced amyloid formation [10]. Thus, while our data do not support the hypothesis that impaired NH 2 -terminal processing of proIAPP leads to amyloid formation in vivo, it remains plausible that increased production of prefibrillar proIAPP aggregates are present in PC2-deficient, human proIAPP-expressing islet grafts and are inducing beta cell dysfunction and death, but that these are not detectable by thioflavin S.…”

“…Misfolded IAPP monomers assemble into oligomeric intermediates, which further generate amyloid fibres containing heparan sulphate proteoglycans, serum amyloid P and apolipoprotein E [4][5][6]. Prefibrillar IAPP species that arise during the transition from monomer to amyloid fibril elicit beta cell dysfunction and apoptosis [7][8][9], and provoke islet inflammation [9][10][11]. Cytotoxic IAPP aggregates mediate beta cell death and dysfunction in type 2 diabetes and in transplanted human islets [10,[12][13][14], although the mechanisms leading to cytotoxicity are poorly understood.…”

The role of caspase-8 in amyloid-induced beta cell death in human and mouse islets

“…Islet amyloid formation in patients with type 2 diabetes contributes to progressive beta cell death [3][4][5]. Unlike in type 2 diabetes, amyloid forms rapidly in cultured [6][7][8] and transplanted human islets [9,10], and this is associated with beta cell dysfunction and death in vitro [6][7][8], and with islet graft failure leading to recurrence of hyperglycaemia in animal models of type 1 diabetes [10][11][12]. Moreover, amyloid deposition associated with reduced beta cell mass has been reported in islet grafts in patients with type 1 diabetes [13,14].…”

The glucagon-like peptide-1 receptor agonist exenatide restores impaired pro-islet amyloid polypeptide processing in cultured human islets: implications in type 2 diabetes and islet transplantation

“…The formation of amyloid in cultured human islets is associated with beta cell dysfunction and apoptosis, both of which are prevented by inhibition of hIAPP aggregation [6,8]. Furthermore, its formation in transplanted islets leads to graft failure and recurrence of hyperglycaemia in animal models of type 1 diabetes [10,13,14].…”