Oxidant-modified amylin fibrils and aggregates alter the inflammatory profile of multiple myeloid cell types, but are non-toxic to islet β cells
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Diabetes mellitus currently affects ∼10% of the population worldwide, with Type 2 predominating, and this incidence is increasing steadily. Both Type 1 and 2 are complex diseases, involving β-cell death and chronic inflammation, but the pathways involved are unresolved. Chronic inflammation is characterized by increased oxidant formation, with this inducing protein modification, altered function and immunogenicity. Amylin, a peptide hormone co-secreted with insulin by β-cells, has attracted considerable interest for its amyloidogenic properties, however, the effects that oxidants have on amylin aggregation and function are poorly understood. Amylin was exposed in vitro to hypochlorous acid, hydrogen peroxide and peroxynitrous acid/peroxynitrite to investigate the formation of post-translational oxidative modifications (oxPTMs, via mass spectrometry) and fibril formation (via transmission electron microscopy). Amylin free acid (AFA) was also examined to investigate the role of the C-terminal amide in amylin. Oxidant exposure led to changes in aggregate morphology and abundance of oxPTMs in a concentration-dependent manner. The toxicity and immunogenic potential of oxidant-modified amylin or AFA on pancreatic islet cells (INS-1E), human monocyte cell line (THP-1) and monocyte-derived dendritic cells (moDCs) were examined using metabolic activity and cytokine assays, and flow cytometry. No significant changes in vitality or viability were detected, but exposure to oxidant-modified amylin or AFA resulted in altered immunogenicity when compared to the native proteins. THP-1 and moDCs show altered expression of activation markers and changes in cytokine secretion. Furthermore, oxidant-treated amylin and AFA promoted maturation of THP-1 and pre-mature moDCs, as determined by changes in size, and maturation markers.
Originalsprog | Engelsk |
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Artikelnummer | 102835 |
Tidsskrift | Redox Biology |
Vol/bind | 65 |
Antal sider | 14 |
ISSN | 2213-2317 |
DOI | |
Status | Udgivet - 2023 |
Bibliografisk note
Funding Information:
This work was funded by the German Federal Ministry of Education and Research ( BMBF ) (grant numbers 03Z22DN11 and 03Z22Di1 to SB), and by the Novo Nordisk Foundation (Laureate grants NNF13OC0004294 and NNF20SA0064214 to MJD). The funding agencies had no role in the design of this study or its execution, analyses, interpretation of the data, or decision to publish results. EFL acknowledges funding from the SFRR-E/Oxygen Club of California (OCC) Early Career Researcher (ECR) Fellowship scheme.
Publisher Copyright:
© 2023 The Authors
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