Phospholipase PLA2G5-triggered hemolysis emerges as a contributor to sepsis lethality.

Despite extensive advances in understanding sepsis pathophysiology, treatment outcomes have not substantially improved. In this issue, Takahama and colleagues identified phospholipase A2 Group V (PLA2G5) as a contributor to sepsis lethality in mouse models of endotoxemia and sepsis. Whole-mouse spatial profiling generated bodywide maps of systemic inflammation and uncovered intestinal goblet cells as a source of pathogenic PLA2G5. Pairs of inflammatory cytokines (TNF and IFN-γ, or TNF and IL-18) induced PLA2G5 expression in goblet cells. Mechanistically, circulating PLA2G5 triggered intravascular hemolysis through its lipolytic activity on erythrocyte membranes and contributed to organ failure and death. PLA2G5's deleterious effects were blocked by specific antibodies and were absent in Pla2g5-deficient mice. In humans with bacterial or fungal sepsis or severe COVID-19, plasma PLA2G5 levels were elevated and predicted disease severity. This discovery highlights the contribution of hemolysis to sepsis, suggesting that PLA2G5 inhibitors, hemoglobin, or heme antagonists could represent valuable therapeutic tools.