Phospholipase PLA2G5-triggered hemolysis emerges as a contributor to sepsis lethality
Jean-Marc Cavaillon
Jean-Marc Cavaillon
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Commentary

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

Abstract

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.

Authors

Jean-Marc Cavaillon

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Figure 1

Contribution of secreted phospholipase A2 Group V (PLA2G5) to red blood cell lysis during sepsis.

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Contribution of secreted phospholipase A2 Group V (PLA2G5) to red blood ...
In mouse models, Takahama et al. (7) showed that sepsis or endotoxemia — mimicked by specific pairs of inflammatory cytokines — induced the production of PLA2G5 by goblet cells within the gut. Once released into the bloodstream, PLA2G5 triggered erythrocyte lysis, leading to the release of hemoglobin and heme, which contributed to organ failure and eventually death. Elevated PLA2G5 levels in humans with bacterial or fungal sepsis or severe COVID-19 predicted disease severity, supporting translation of these findings to clinical understanding of sepsis.