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

Area of Science:

• Sepsis Pathophysiology
• Inflammation Biology
• Hemolysis Mechanisms

Background:

• Sepsis treatment outcomes remain poor despite advances in understanding its complex pathophysiology.
• Identifying novel molecular contributors to sepsis lethality is crucial for developing effective therapies.

Purpose of the Study:

• To investigate the role of phospholipase A2 Group V (PLA2G5) in sepsis lethality.
• To elucidate the cellular sources and mechanisms by which PLA2G5 contributes to sepsis progression.

Main Methods:

• Utilized mouse models of endotoxemia and sepsis.
• Employed whole-mouse spatial profiling to map systemic inflammation.
• Investigated PLA2G5 induction by inflammatory cytokines (TNF, IFN-γ, IL-18) in intestinal goblet cells.
• Assessed the impact of PLA2G5 on intravascular hemolysis and organ failure.
• Evaluated therapeutic interventions including specific antibodies and PLA2G5 deficiency.

Main Results:

• Identified intestinal goblet cells as a source of pathogenic PLA2G5, induced by specific cytokine pairs.
• Demonstrated that circulating PLA2G5 causes intravascular hemolysis via lipolytic activity on erythrocyte membranes.
• Showed that PLA2G5 contributes to organ failure and mortality in sepsis models.
• Confirmed that PLA2G5 inhibition or deficiency mitigates sepsis severity.
• Observed elevated plasma PLA2G5 levels in human sepsis and severe COVID-19 patients, correlating with disease severity.

Conclusions:

• PLA2G5 is a key mediator of sepsis lethality, primarily through inducing hemolysis.
• Elevated PLA2G5 levels in human sepsis and severe COVID-19 suggest its clinical relevance.
• PLA2G5 inhibitors, hemoglobin, or heme antagonists represent potential therapeutic avenues for sepsis.