Mechanism for the attenuation of neutrophil and complement hyperactivity by MSC exosomes

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Mechanism for the attenuation of neutrophil and complement hyperactivity by MSC exosomes
Title:
Mechanism for the attenuation of neutrophil and complement hyperactivity by MSC exosomes
Journal Title:
Cytotherapy
Publication Date:
15 February 2022
Citation:
Loh, J. T., Zhang, B., Teo, J. K. H., Lai, R. C., Choo, A. B. H., Lam, K.-P., & Lim, S. K. (2022). Mechanism for the attenuation of neutrophil and complement hyperactivity by MSC exosomes. Cytotherapy. https://doi.org/10.1016/j.jcyt.2021.12.003
Abstract:
Complements and neutrophils are two key players of the innate immune system that are widely implicated as drivers of severe COVID-19 pathogenesis, as evident by the direct correlation of respiratory failure and mortality with elevated levels of terminal complement complex C5b-9 and neutrophils. In this study, we identified a feed-forward loop between complements and neutrophils that could amplify and perpetuate the cytokine storm seen in severe SARS-CoV-2infected patients. We observed for the first time that the terminal complement activation complex C5b-9 directly triggered neutrophil extracellular trap (NET) release and interleukin (IL)-17 production by neutrophils. This is also the first report that the production of NETs and IL- 17 induced by C5b-9 assembly on neutrophils could be abrogated by mesenchymal stem cell (MSC) exosomes. Neutralizing anti-CD59 antibodies abolished this abrogation. Based on our findings, we hypothesize that MSC exosomes could alleviate the immune dysregulation in acute respiratory failure, such as that observed in severe COVID-19 patients, by inhibiting complement activation through exosomal CD59, thereby disrupting the feed-forward loop between complements and neutrophils to inhibit the amplification and perpetuation of inflammation during SARS-CoV-2 infection.
License type:
Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)
Funding Info:
This research / project is supported by the A*STAR - Industry Alignment Fund - Pre-Positioning (IAF-PP)
Grant Reference no. : H19H6a0026
Description:
© 2022 International Society for Cell & Gene Therapy. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/)
ISSN:
1465-3249