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

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 t...

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Autores principales: Loh, Jia Tong, Zhang, Bin, Teo, Joey Kay Hui, Lai, Ruenn Chai, Choo, Andre Boon Hwa, Lam, Kong-Peng, Lim, Sai Kiang
Formato: Online Artículo Texto
Lenguaje:English
Publicado: International Society for Cell & Gene Therapy. Published by Elsevier Inc. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8843421/
https://www.ncbi.nlm.nih.gov/pubmed/35177337
http://dx.doi.org/10.1016/j.jcyt.2021.12.003
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author Loh, Jia Tong
Zhang, Bin
Teo, Joey Kay Hui
Lai, Ruenn Chai
Choo, Andre Boon Hwa
Lam, Kong-Peng
Lim, Sai Kiang
author_facet Loh, Jia Tong
Zhang, Bin
Teo, Joey Kay Hui
Lai, Ruenn Chai
Choo, Andre Boon Hwa
Lam, Kong-Peng
Lim, Sai Kiang
author_sort Loh, Jia Tong
collection PubMed
description 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-2–infected 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.
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spelling pubmed-88434212022-02-15 Mechanism for the attenuation of neutrophil and complement hyperactivity by MSC exosomes Loh, Jia Tong Zhang, Bin Teo, Joey Kay Hui Lai, Ruenn Chai Choo, Andre Boon Hwa Lam, Kong-Peng Lim, Sai Kiang Cytotherapy Full Length Article 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-2–infected 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. International Society for Cell & Gene Therapy. Published by Elsevier Inc. 2022-07 2022-02-15 /pmc/articles/PMC8843421/ /pubmed/35177337 http://dx.doi.org/10.1016/j.jcyt.2021.12.003 Text en © 2022 International Society for Cell & Gene Therapy. Published by Elsevier Inc. Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active.
spellingShingle Full Length Article
Loh, Jia Tong
Zhang, Bin
Teo, Joey Kay Hui
Lai, Ruenn Chai
Choo, Andre Boon Hwa
Lam, Kong-Peng
Lim, Sai Kiang
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
title_full Mechanism for the attenuation of neutrophil and complement hyperactivity by MSC exosomes
title_fullStr Mechanism for the attenuation of neutrophil and complement hyperactivity by MSC exosomes
title_full_unstemmed Mechanism for the attenuation of neutrophil and complement hyperactivity by MSC exosomes
title_short Mechanism for the attenuation of neutrophil and complement hyperactivity by MSC exosomes
title_sort mechanism for the attenuation of neutrophil and complement hyperactivity by msc exosomes
topic Full Length Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8843421/
https://www.ncbi.nlm.nih.gov/pubmed/35177337
http://dx.doi.org/10.1016/j.jcyt.2021.12.003
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