Islet Amyloid Polypeptide Triggers Limited Complement Activation and Binds Complement Inhibitor C4b-binding Protein, Which Enhances Fibril Formation

Abstract

Islet amyloid polypeptide (IAPP) is synthesized in pancreatic␤-cells and co-secreted with insulin. Aggregation and formation of IAPP-amyloid play a critical role in ␤-cell death in type 2 diabetic patients. Because A␤-fibrils in Alzheimer disease activate the complement system, we have here investigated specific interactions between IAPP and complement factors. IAPP fibrils triggered limited activation of complement in vitro, involving both the classical and the alternative pathways. Direct binding assays confirmed that IAPP fibrils interact with globular head domains of complement initiator C1q. Furthermore, IAPP also bound complement inhibitors factor H and C4b-binding protein (C4BP). Recombinant C4BP mutants were used to show that complement control protein (CCP) domains 8 and 2 of the ␣-chain were responsible for the strong, hydrophobic binding of C4BP to IAPP. Immunostaining of pancreatic sections from type 2 diabetic patients revealed the presence of complement factors in the islets and varying degree of co-localization between IAPP fibrils and C1q, C3d, as well as C4BP and factor H but not membrane attack complex. Furthermore, C4BP enhanced formation of IAPP fibrils in vitro. We conclude that C4BP binds to IAPP thereby limiting complement activation and may be enhancing formation of IAPP fibrils from cytotoxic oligomers.

Il10 Deficiency Rebalances Innate Immunity to Mitigate Alzheimer-Like Pathology

“…Interestingly, genes up-regulated in brains of patients with late onset AD such as Tyrobp , Trem2 and C4b (Brouwers et al, 2012; McGeer et al, 1989; Zhang et al, 2013) were decreased in brains of Il10 deficient APP/PS1 mice. Along similar lines, previous studies have shown that TLR2 and C4b bind Aβ and trigger microglial activation (Richard et al, 2008) and Aβ fibril formation (Sjolander et al, 2012; Trouw et al, 2008), and APP/PS1 + Il10 −/− brains had decreased expression of both genes. Strikingly, Chakrabarty and coworkers have demonstrated that adeno-associated viral expression of Il10 in brains of APP transgenic mice leads to age-dependent up-regulation of Cxcl10 , Tlr2 , C4b and C3ar1 transcripts (Chakrabarty et al, 2015).…”

The role of the complement system in metabolic organs and metabolic diseases

“…A further hallmark of the islets in type 2 diabetic patients is the ectopic accumulation of extracellular amyloid fibrils, which is partially mediated by excess free fatty acids (FFA) and exerts cytotoxic effects on β-cells [31, 32]. Intriguingly, amyloid fibrils can trigger local complement activation via C1q [33, 34], thereby facilitating local inflammation and macrophage activation, ultimately promoting β-cell death. Nevertheless, immunohistology studies have shown that there is limited MAC deposition on the islets that colocalizes with amyloid polypeptide fibrils [34].…”

“…Intriguingly, amyloid fibrils can trigger local complement activation via C1q [33, 34], thereby facilitating local inflammation and macrophage activation, ultimately promoting β-cell death. Nevertheless, immunohistology studies have shown that there is limited MAC deposition on the islets that colocalizes with amyloid polypeptide fibrils [34]. This limited MAC deposition could be attributed to the fact that amyloid fibrils interact with C4BP and fH, which inhibit complement activation[34].…”

“…Nevertheless, immunohistology studies have shown that there is limited MAC deposition on the islets that colocalizes with amyloid polypeptide fibrils [34]. This limited MAC deposition could be attributed to the fact that amyloid fibrils interact with C4BP and fH, which inhibit complement activation[34]. Thus, amyloid fibrils may also limit complement activity in the islets.…”

“…In contrast, increased complement action can contribute to metabolic pathology. In the pancreas, complement activation can contribute to β-cell apoptosis in T1DM [41, 43, 44, 53] and T2DM [33, 34]. In obesity, anaphylatoxins promote leukocyte recruitment to the AT, thereby facilitating inflammation and the associated insulin resistance [83, 84, 86].…”