Published papers

Secreted phospholipase A2-IIA (sPLA2-IIA) hydrolyzes phospholipids to liberate lysophospholipids and fatty acids. Given its poor activity toward eukaryotic cell membranes, its role in the generation of proinflammatory lipid mediators is unclear. Conversely, sPLA2-IIA efficiently hydrolyzes bacterial membranes. Here, we show that sPLA2-IIA affects the immune system by acting on the intestinal microbial flora. Using mice overexpressing transgene-driven human sPLA2-IIA, we found that the intestinal microbiota was critical for both induction of an immune phenotype and promotion of inflammatory arthritis. The expression of sPLA2-IIA led to alterations of the intestinal microbiota composition, but housing in a more stringent pathogen-free facility revealed that its expression could affect the immune system in the absence of changes to the composition of this flora. In contrast, untargeted lipidomic analysis focusing on bacteria-derived lipid mediators revealed that sPLA2-IIA could profoundly alter the fecal lipidome. The data suggest that a singular protein, sPLA2-IIA, produces systemic effects on the immune system through its activity on the microbiota and its lipidome.

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. (Figure presented.)