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 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 termi-nal 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) exo-somes. 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 per-petuation of inflammation during SARS-CoV-2 infection.(c) 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/)

Automated summary

This study identified a feed-forward loop between complements and neutrophils that contributes to the cytokine storm in severe SARS-CoV-2-infected patients. It was observed that the terminal complement activation complex C5b-9 directly triggers neutrophil extracellular trap (NET) release and interleukin (IL)-17 production by neutrophils. Mesenchymal stem cell (MSC) exosomes were found to inhibit this loop by suppressing complement activation through exosomal CD59, suggesting their potential role in alleviating immune dysregulation and inflammation in acute respiratory failure.