Innate immunity in diabetes mellitus. Complement components C4BP and C3 promote survival of β cells under metabolic challenges

Sammanfattning: The Complement system is a main effector mechanism of the innate immune system, acting to enhance clearance of pathogens, but also aids removal of biological debris from the body, including immunocomplexes, apoptotic/necrotic cells and protein aggregates. Complement regulators serve to prevent excessive inflammation and their interaction with the same materials targeted by the complement system results in ‘silent’ cleaning of wastes. Type 2 diabetes (T2D) is characterized by insulin resistance in peripheral tissues resulting in an initial compensatory upregulation of insulin production but ultimately leading to failure of blood glucose homeostasis and death of insulinsecreting pancreatic β-cells. T2D is now understood to have several components, which drives pancreatic islet dysfunction: high glucose concentration, proinflammatory cytokines, long chain free fatty acids, increased insulin synthesis demand and increased exposure to islet amyloid polypeptide (IAPP). IAPP a hormone co-secreted with insulin from pancreatic β-cells is capable to form amyloid and intermediate species; oligomers that are highly cytotoxic for β-cells. IAPP oligomers have been also shown to activate the NOD-like receptor pyrin domain containing-3 (NLRP3) inflammasome leading to production of the pro-inflammatory cytokine IL-1β, which in high concretions is a driver of β-cell pathology. Previously we described binding of complement regulator C4-binding protein (C4BP) to IAPP amyloid that affected transition of IAPP monomers and oligomers to mature IAPP fibrils.Therefore, we hypothesized that C4BP might inhibit IAPP oligomer-induced death of β-cells, and limit inflammasome activation and IL-1β secretion secondary to β-cell failure. Presence of C4BP with IAPP monomers, which tend to assemble into oligomers and amyloid, resulted in better survival of cultured rat insulinoma INS-1 β-cells compared to cells treated with IAPP alone. Similarly, addition of C4BP with IAPP to macrophages limited IAPP-dependent inflammasome activation and IL-1β release, ensuring protection of β-cells against IL-1β-driven toxicity. Dysregulated autophagy in β-cells coincides with failure of β-cells as well. Autophagy, a housekeeping activity,necessary for elimination and recycling of unwanted cellular components, supports β-cell health under metabolic challenges. A hub of the complement protein cascade, complement component 3 (C3) has been found to be highly expressed in human pancreatic islets with increased expression after exposure to β-cell specific stressors: IL-1β, palmitic acid (PA) and IAPP. We found that C3 regulates the process of autophagy and improves viability of INS-1 cells under IAPP and PA treatments. Furthermore, we found C3 to be cytoprotective against IL-1β induced death of β-cells. IL-1β driven upregulation of proapoptotic signalling does not seem to be dependent on canonical autophagy, but surprisingly intracellular/cytosolic C3 conferred protection to β-cells exposed to IL-1β.