Islet amyloid polypeptide triggers limited complement activation and binds complement inhibitor C4b-binding protein, which enhances fibril formation

J Sjölander,G.T Westermark,E Renström,A.M Blom

doi:10.1016/j.molimm.2011.06.389

Abstract

Islet amyloid polypeptide (IAPP) is synthesized in pancreatic β-cells and co-secreted with insulin. Aggregation and formation of IAPP-amyloid play a critical role in β-cell death in type 2 diabetic patients. Because Aβ-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 α-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.

Highlights

Deposition of amyloid is one of the main pathological characteristics in patients with type 2 diabetes (T2D).2 These amyloid deposits were first named islet amyloid because of its location inside the islets of Langerhans and later found to consist of the polypeptide hormone, islet amyloid polypeptide (IAPP) [1], which is expressed by the ␤-cell and co-secreted together with insulin [2, 3]
Complement Factors C1q, C3d, C5b-9, and Complement Inhibitors C4b-binding protein (C4BP) and factor H (FH) Co-localize to Various Extents with IAPP and IAPP Fibrils in Human Pancreatic Tissue—Because human IAPP was reported to trigger complement activation via the classical pathway [13], amyloid-containing pancreatic sections from patients with T2D were stained for complement components
This indicates that FH and membrane attack complex (MAC) are present in the islets but not exclusively bound to the mature IAPP fibrils

Summary

Introduction

Deposition of amyloid is one of the main pathological characteristics in patients with type 2 diabetes (T2D). These amyloid deposits were first named islet amyloid because of its location inside the islets of Langerhans and later found to consist of the polypeptide hormone, islet amyloid polypeptide (IAPP) [1], which is expressed by the ␤-cell and co-secreted together with insulin [2, 3]. Oligomers have the ability to incorporate into membranes and form ion-leaking pores [10], which may be the reason for their cytotoxicity In this scenario, mature amyloid fibrils appear to be a way to neutralize toxic oligomers safely. The complement cascade is organized in three pathways of which the classical route is triggered by C1 complex binding to immune complexes causing activation of C4 and C2, which together form the classical C3 convertase [14]. C4BP and FH circulate in blood and act on the level of C3/C5 convertases [14], and both inhibitors contain complement control protein (CCP) domains. The aim of the present study was to elucidate the interactions between complement factors and IAPP fibrils in relation to T2D

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