The human serum protein C4b-binding protein inhibits pancreatic IAPP-induced inflammasome activation

Diabetologia
Klaudia KulakBen C King

Abstract

Inflammasome activation and subsequent IL-1β production is a driver of islet pathology in type 2 diabetes. Oligomers, but not mature amyloid fibrils, of human islet amyloid polypeptide (IAPP), which is co-secreted with insulin, trigger NOD-like receptor pyrin domain containing-3 (NLRP3) inflammasome activation. C4b-binding protein (C4BP), present in serum, binds to IAPP and affects transition of IAPP monomers and oligomers to amyloid fibrils. We therefore hypothesised that C4BP inhibits IAPP-mediated inflammasome activation and IL-1β production. Macrophages were exposed to IAPP in the presence or absence of plasma-purified human C4BP, and inflammasome activation was assessed by IL-1β secretion as detected by ELISA and reporter cell lines. IAPP fibrillation was assessed by thioflavin T assay. Uptake of IAPP-C4BP complexes and their effects on phagolysosomal stability were assessed by flow cytometry and confocal microscopy. The effect of C4BP regulation of IAPP-mediated inflammasome activation on beta cell function was assessed using a clonal rat beta cell line. Immunohistochemistry was used to examine the association of IAPP amyloid deposits and macrophage infiltration in isolated human and mouse pancreatic islets, and expressio...Continue Reading

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Citations

Jun 3, 2021·International Journal of Molecular Sciences·Safia CostesMagalie A Ravier
Jun 24, 2021·Seminars in Immunopathology·B C King, A M Blom
Jun 28, 2019·Chemical Research in Toxicology·Adam HellerKeith A Friedman
Oct 13, 2021·Journal of Cellular Physiology·Carine MarmentiniMirian A Kurauti

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Methods Mentioned

BETA
ELISA
flow cytometry
PCR
electrophoresis
electron microscopy
Confocal microscopy
transgenic

Software Mentioned

Caslo
GraphPad Prism

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