Within the secreted phospholipase A2<\/sub> (sPLA2<\/sub>) family, group X sPLA2<\/sub> (sPLA2<\/sub>-X) has the highest capacity to hydrolyze cellular membranes and has long been thought to promote inflammation by releasing arachidonic acid, a precursor of pro-inflammatory eicosanoids. Unexpectedly, we found that transgenic mice globally overexpressing human sPLA2<\/sub>-X (PLA2G10<\/em>-Tg) displayed striking immunosuppressive and lean phenotypes with lymphopenia and increased M2-like macrophages, accompanied by marked elevation of free \u03c93 polyunsaturated fatty acids (PUFAs) and their metabolites. Studies using Pla2g10<\/em>-deficient mice revealed that endogenous sPLA2<\/sub>-X, which is highly expressed in the colon epithelium and spermatozoa, mobilized \u03c93 PUFAs or their metabolites to protect against dextran sulfate-induced colitis and to promote fertilization, respectively. In colitis, sPLA2<\/sub>-X deficiency increased colorectal expression of Th17 cytokines, and \u03c93 PUFAs attenuated their production by lamina propria cells partly through the fatty acid receptor GPR120. In comparison, cytosolic phospholipase A2<\/sub> (cPLA2<\/sub>\u03b1) protects from colitis by mobilizing \u03c96 arachidonic acid metabolites, including prostaglandin E2<\/sub>. Thus, our results underscore a previously unrecognized role of sPLA2<\/sub>-X as an \u03c93 PUFA mobilizer in vivo<\/em>, segregated mobilization of \u03c93 and \u03c96 PUFA metabolites by sPLA2<\/sub>-X and cPLA2<\/sub>\u03b1, respectively, in protection against colitis, and the novel role of a particular sPLA2<\/sub>-X-driven PUFA in fertilization.<\/p>\n\n\n\n Keywords: <\/strong>arachidonic acid (AA) (ARA), colitis, inflammation, lipid metabolism, membrane, Phospholipase A, polyunsaturated fatty acid (PUFA), prostaglandin, sperm <\/p>\n\n\n\n