Abstract
Beta cell failure and apoptosis following islet inflammation have been associated with autoimmune type 1 diabetes pathogenesis. As conveyors of biological active material, extracellular vesicles (EV) act as mediators in communication with immune effectors fostering the idea that EV from inflamed beta cells may contribute to autoimmunity. Evidence accumulates that beta exosomes promote diabetogenic responses, but relative contributions of larger vesicles as well as variations in the composition of the beta cell's vesiculome due to environmental changes have not been explored yet. Here, we made side-by-side comparisons of the phenotype and function of apoptotic bodies (AB), microvesicles (MV) and small EV (sEV) isolated from an equal amount of MIN6 beta cells exposed to inflammatory, hypoxic or genotoxic stressors. Under normal conditions, large vesicles represent 93% of the volume, but only 2% of the number of the vesicles. Our data reveal a consistently higher release of AB and sEV and to a lesser extent of MV, exclusively under inflammatory conditions commensurate with a 4-fold increase in the total volume of the vesiculome and enhanced export of immune-stimulatory material including the autoantigen insulin, microRNA, and cytokines. Whilst inflammation does not change the concentration of insulin inside the EV, specific Toll-like receptor-binding microRNA sequences preferentially partition into sEV. Exposure to inflammatory stress engenders drastic increases in the expression of monocyte chemoattractant protein 1 in all EV and of interleukin-27 solely in AB suggesting selective sorting toward EV subspecies. Functional in vitro assays in mouse dendritic cells and macrophages reveal further differences in the aptitude of EV to modulate expression of cytokines and maturation markers. These findings highlight the different quantitative and qualitative imprints of environmental changes in subpopulations of beta EV that may contribute to the spread of inflammation and sustained immune cell recruitment at the inception of the (auto-) immune response.
Highlights
Type 1 diabetes (T1D) is an autoimmune disease caused by the destruction of the insulin-producing beta cells in the pancreas leading to chronic hyperglycaemia and serious longterm complications such as cardiovascular disease, neuropathy, nephropathy and blindness [reviewed in [1]]
Primary islet inflammatory events have been associated with beta cell stress and failure at the origin of T1D pathogenesis [40, 41]
With the aim to study the impact of cellular stress on the beta vesicular secretome, murine MIN6 beta cells were either left untreated (CTL) or exposed to a cocktail of mild doses of proinflammatory cytokines (CK) encountered at disease initiation
Summary
Type 1 diabetes (T1D) is an autoimmune disease caused by the destruction of the insulin-producing beta cells in the pancreas leading to chronic hyperglycaemia and serious longterm complications such as cardiovascular disease, neuropathy, nephropathy and blindness [reviewed in [1]]. Pathogenesis of T1D is characterized by inflammatory events in the beta cell microenvironment causing innate immune activation followed by progressive infiltration of the islets of Langerhans in the endocrine pancreas by auto-reactive cytotoxic T-lymphocytes. Disease etiology has only partially been elucidated, but results from a complex interplay between genetic and environmental factors collectively engendering functional defects in the immune system and the beta cell itself. By interaction with built-in sensors, these misfolded proteins trigger the unfolded protein response (UPR), a signaling pathway that aims to restore homeostasis by enhancing the cell’s folding capacity and translational attenuation. Beta cell stress and apoptosis has been associated with T1D pathogenesis [5, 6], yet, how stressed beta cells trigger innate immune responses at disease initiation has not been fully elucidated
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