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Background <p>Severe COVID-19 is marked by a dysregulated inflammatory response, known as a cytokine storm, resulting in acute respiratory distress syndrome (ARDS) and multiple organ failure. Mesenchymal stem cell-derived exosomes (MSC-Exos) have demonstrated potential as immunomodulatory agents. This work investigates the possibility of MSC-Exos to mitigate excessive inflammation in COVID-19 by targeting the mitogen-activated protein kinase (MAPK) signalling pathway.</p> Methodology <p>We integrated molecular docking analysis between TGF-β and Annexin A1 as exosomal proteins and key component proteins of the MAPK pathway (p38, ERK1/2, JNK1). The in-silico results were then validated in vivo using a Syrian hamster model of SARS-CoV-2 infection. Quantitative PCR (qPCR), western blotting, and histological examination were employed to evaluate the effects of MSC-Exos therapy on MAPK pathway activation, cytokine production, and lung tissue pathology.</p> Results <p>The in-silico study revealed extensive hydrogen bonding and hydrophobic interactions at the protein–protein interfaces between exosomal proteins and MAPK components. These interactions suggest that exosomal proteins may modulate MAPK signaling pathways. In vivo, MSC-Exos administration led to marked downregulation of pivotal genes in the MAPK signaling pathway (MEKK1, MEKK2, MEKK3), diminished phosphorylation of JNK1, p38, and ERK1/2, and lowered production of pro-inflammatory cytokines (IL-1β, IL-6, TNF-α). Histopathological examination demonstrated ameliorated lung tissue structure, characterized by diminished alveolar wall thickness and decreased immune cell infiltration.</p> Conclusion <p>MSC-Exos elicit immunomodulatory effects in SARS-CoV-2-Infected hamsters, partially by directly targeting and blocking the MAPK signaling pathway. These findings offer a compelling justification for the clinical assessment of MSC-Exos as a therapeutic approach to alleviate the cytokine storm and enhance outcomes in severe COVID-19 by targeting the ACE2-Independent pathway.</p> Graphical abstract <p></p>

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Mesenchymal stem cell derived exosomes mitigate COVID-19 cytokine storm via Annexin A1 and TGF-β mediated MAPK pathway inhibition

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年5月8日

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  • Nesrine Ebrahim,
  • Hajir A. Al Saihati,
  • Arigue A. Dessouky,
  • Yasmeen Mohammed Ismail,
  • Ashraf A. Shamaa,
  • Shereen A. Mohamed,
  • Mohamed E. Mohamed,
  • Nermine Nosseir,
  • Mohamed Ahmed Eladl,
  • Gianpiero Di Leva,
  • Omnia A. Badr

摘要

Background

Severe COVID-19 is marked by a dysregulated inflammatory response, known as a cytokine storm, resulting in acute respiratory distress syndrome (ARDS) and multiple organ failure. Mesenchymal stem cell-derived exosomes (MSC-Exos) have demonstrated potential as immunomodulatory agents. This work investigates the possibility of MSC-Exos to mitigate excessive inflammation in COVID-19 by targeting the mitogen-activated protein kinase (MAPK) signalling pathway.

Methodology

We integrated molecular docking analysis between TGF-β and Annexin A1 as exosomal proteins and key component proteins of the MAPK pathway (p38, ERK1/2, JNK1). The in-silico results were then validated in vivo using a Syrian hamster model of SARS-CoV-2 infection. Quantitative PCR (qPCR), western blotting, and histological examination were employed to evaluate the effects of MSC-Exos therapy on MAPK pathway activation, cytokine production, and lung tissue pathology.

Results

The in-silico study revealed extensive hydrogen bonding and hydrophobic interactions at the protein–protein interfaces between exosomal proteins and MAPK components. These interactions suggest that exosomal proteins may modulate MAPK signaling pathways. In vivo, MSC-Exos administration led to marked downregulation of pivotal genes in the MAPK signaling pathway (MEKK1, MEKK2, MEKK3), diminished phosphorylation of JNK1, p38, and ERK1/2, and lowered production of pro-inflammatory cytokines (IL-1β, IL-6, TNF-α). Histopathological examination demonstrated ameliorated lung tissue structure, characterized by diminished alveolar wall thickness and decreased immune cell infiltration.

Conclusion

MSC-Exos elicit immunomodulatory effects in SARS-CoV-2-Infected hamsters, partially by directly targeting and blocking the MAPK signaling pathway. These findings offer a compelling justification for the clinical assessment of MSC-Exos as a therapeutic approach to alleviate the cytokine storm and enhance outcomes in severe COVID-19 by targeting the ACE2-Independent pathway.

Graphical abstract