Secreted phospholipase PLA2G5 acts as a hemolytic factor in sepsis.

Summary

PLA2G5 is induced in intestinal goblet cells during sepsis and circulates to trigger intravascular hemolysis via lipolytic activity on erythrocyte membranes. Genetic deletion or antibody neutralization protects mice from lethal sepsis, with improved iron homeostasis. In human sepsis (bacterial, fungal, viral), plasma PLA2G5 is elevated and predicts severity and mortality.

Key Findings

• PLA2G5 is induced in colon cell types during sepsis and becomes a circulating factor.
• Pla2g5 knockout mice and mice treated with a PLA2G5-neutralizing antibody are protected from lethal sepsis.
• Circulating PLA2G5 causes intravascular hemolysis via lipolysis of erythrocyte membranes, impairing iron homeostasis.
• Human sepsis patients exhibit elevated plasma PLA2G5 levels that predict disease severity and mortality.
• Antibody treatment increases splenic red pulp macrophages and improves iron regulation.

Clinical Implications

Measuring plasma PLA2G5 could aid risk stratification. Therapeutic strategies targeting PLA2G5 or mitigating hemolysis (e.g., heme/hemoglobin scavengers) warrant investigation as adjuncts in severe sepsis.

Limitations

• Predominantly murine models (endotoxemia and sepsis) may not capture full human heterogeneity.
• Interventional efficacy of PLA2G5 blockade has not been tested in clinical trials; human cohort sample sizes are not detailed.

Future Directions

Prospectively validate PLA2G5 as a biomarker; develop selective PLA2G5 inhibitors/antibodies; test combination strategies with heme scavengers in large-animal models and early-phase clinical trials.