Secretory phospholipase A₂-IIA targets bacterial extracellular vesicles to modulate immune signaling

Secretory phospholipase A₂-IIA (sPLA₂-IIA) is a bactericidal enzyme that hydrolyzes membrane phospholipids, releasing lipid metabolites that can affect inflammation. sPLA₂-IIA exhibits poor activity toward eukaryotic cells but preferentially targets gram-positive bacterial membranes. While sPLA₂-IIA is constitutively expressed in the intestine and upregulated by inflammation in various bodily fluids, its precise physiological substrates remain debated. Intriguingly, sPLA₂-IIA can modulate the intestinal lipidome without altering the microbiota composition. Here, we investigated whether sPLA₂-IIA could use membranes from bacterial extracellular vesicles (bEVs) as alternative substrates to modulate immune signaling. We found that bEVs from both Staphylococcus aureus and Escherichia coli could mitigate the bactericidal effects of sPLA₂-IIA on gram-positive bacteria. Enzymatic hydrolysis of bacteria, bEVs and fecal extracellular vesicles released distinct lipid metabolites and differentially impacted Toll-like receptor activation. These findings suggest that sPLA₂-IIA can use bEVs as substrates and modulate inflammatory signaling through the generation of pathogen-associated molecular patterns, thus linking bacterial lipid metabolism to host immune response.