Mitochondrial activity promotes neutrophil degranulation and endothelial dysfunction in systemic infections
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Abstract
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. 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.
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Strength of evidence
Reviewers: B Mishra (Albany Medical College) | 📘📘📘📘📘
B Yipp (University of Calgary) | 📒📒📒◻️◻️ -
Bryan Yipp
Review 2: "Mitochondrial Activity Promotes Neutrophil Degranulation and Endothelial Dysfunction in Systemic Infections"
Reviewers rated the preprint as strong to potentially informative, highlighting the cross-disease comparison and integration of mitochondrial biology with neutrophil immunopathology, while noting limits from small samples and cell heterogeneity.
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Bibhuti Mishra
Review 1: "Mitochondrial Activity Promotes Neutrophil Degranulation and Endothelial Dysfunction in Systemic Infections"
Reviewers rated the preprint as strong to potentially informative, highlighting the cross-disease comparison and integration of mitochondrial biology with neutrophil immunopathology, while noting limits from small samples and cell heterogeneity.
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