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<p>Neutrophils are essential for defense against pathogens but excessive activation in systemic infections can drive immunopathology. We show that neutrophil degranulation can induce endothelial dysfunction via degradation of the glycocalyx and increase of endothelial permeability. To identify targetable pathways regulating neutrophil degranulation in severe inflammation, we compared the proteomes of neutrophils isolated from patients with severe malaria and sepsis. We found significant upregulation of mitochondrial pathways, which was accompanied by increased rates of mitochondrial respiration and was linked to neutrophil immaturity. Malaria induced mitochondrial fusion and networking, while sepsis was associated with mitochondrial biogenesis. Immature neutrophils in both infections produced elevated levels of mitochondrial ROS, which enhanced release of primary and secondary granules via reorganization of cortical actin. Our study provides a mechanistic explanation for the hyperinflammatory nature of immature neutrophils and points to pharmacological scavenging of mitochondrial ROS as a potential therapeutic strategy to reduce endothelial damage in severe inflammation.</p>

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Mitochondrial activity promotes neutrophil degranulation and endothelial dysfunction in systemic infections

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年5月27日

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  • Przemysław Zakrzewski,
  • Christopher M Rice,
  • Claire Naveh,
  • Isaac Dowell,
  • Kathryn Fleming,
  • Aravind V Ramesh,
  • Rachel Jones,
  • Pedro L Moura,
  • Drinalda Cela,
  • Sarah Groves,
  • Stephanie Fletcher-Jones,
  • Yohance Victory,
  • Mainga Bhima,
  • Stefan Ebmeier,
  • Laura Carey,
  • Matthew Butler,
  • Simon C Satchell,
  • Ase Berg,
  • Nadia Palolite,
  • James Nyirenda,
  • Watipenge Nyasulu,
  • Isabel Zgambo,
  • Charalampos Attipa,
  • Linda Wooldridge,
  • Andrew D Davidson,
  • Aubrey Cunnington,
  • Christopher A Moxon,
  • Borko Amulic

摘要

Neutrophils are essential for defense against pathogens but excessive activation in systemic infections can drive immunopathology. We show that neutrophil degranulation can induce endothelial dysfunction via degradation of the glycocalyx and increase of endothelial permeability. To identify targetable pathways regulating neutrophil degranulation in severe inflammation, we compared the proteomes of neutrophils isolated from patients with severe malaria and sepsis. We found significant upregulation of mitochondrial pathways, which was accompanied by increased rates of mitochondrial respiration and was linked to neutrophil immaturity. Malaria induced mitochondrial fusion and networking, while sepsis was associated with mitochondrial biogenesis. Immature neutrophils in both infections produced elevated levels of mitochondrial ROS, which enhanced release of primary and secondary granules via reorganization of cortical actin. Our study provides a mechanistic explanation for the hyperinflammatory nature of immature neutrophils and points to pharmacological scavenging of mitochondrial ROS as a potential therapeutic strategy to reduce endothelial damage in severe inflammation.