The interaction of secreted phospholipase A2-IIA with the microbiota alters its lipidome and promotes inflammation

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 impacts on 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. Identification of the microbiota composition of WT and sPLA2-IIATGN mice in different conditions. Conditions 1: at three different timepoint of a fecal microbiota transplantation: initial flora (Day 0), reconstituted flora (Day 21) and flora during arthritis (Day 29) (n = 5-7). Condition 2: in mice housed in an SPF animal facility (n = 7-8). Condition 3: in mice housed in an Elite SPF+ animal facility at two timepoints: at 14 weeks of age and at 14 months of age.