Microenvironment-based alterations in phenotypes of mast cells influence the susceptibility to anaphylaxis, yet the mechanisms underlying proper maturation of mast cells toward an anaphylaxis-sensitive phenotype are incompletely understood. Here we report that PLA2G3, a mammalian homolog of anaphylactic bee venom phospholipase A2, regulates this process. PLA2G3 secreted from mast cells is coupled with fibroblastic lipocalin-type PGD2 synthase (L-PGDS) to provide PGD2, which facilitates mast-cell maturation via PGD2 receptor DP1. Mice lacking PLA2G3, L-PGDS or DP1, mast cell–deficient mice reconstituted with PLA2G3-null or DP1-null mast cells, or mast cells cultured with L-PGDS–ablated fibroblasts exhibited impaired maturation and anaphylaxis of mast cells. Thus, we describe a lipid-driven PLA2G3–L-PGDS–DP1 loop that drives mast cell maturation.

Within the secreted phospholipase A 2 (sPLA 2 ) family, group X sPLA 2 (sPLA 2 -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 sPLA 2 -X (PLA2G10-Tg) displayed striking immunosuppressive and lean phenotypes with lymphopenia and increased M2-like macrophages, accompanied by marked elevation of free 3 polyunsaturated fatty acids (PUFAs) and their metabolites. Studies using Pla2g10-deficient mice revealed that endogenous sPLA 2 -X, which is highly expressed in the colon epithelium and spermatozoa, mobilized 3 PUFAs or their metabolites to protect against dextran sulfate-induced colitis and to promote fertilization, respectively. In colitis, sPLA 2 -X deficiency increased colorectal expression of Th17 cytokines, and 3 PUFAs attenuated their production by lamina propria cells partly through the fatty acid receptor GPR120. In comparison, cytosolic phospholipase A 2 (cPLA 2 ␣) protects from colitis by mobilizing 6 arachidonic acid metabolites, including prostaglandin E 2 . Thus, our results underscore a previously unrecognized role of sPLA 2 -X as an 3 PUFA mobilizer in vivo, segregated mobilization of 3 and 6 PUFA metabolites by sPLA 2 -X and cPLA 2 ␣, respectively, in protection against colitis, and the novel role of a particular sPLA 2 -X-driven PUFA in fertilization.

Within the phospholipase A (PLA) family that hydrolyzes phospholipids to yield fatty acids and lysophospholipids, secreted PLA (sPLA) enzymes comprise the largest group containing 11 isoforms in mammals. Individual sPLAs exhibit unique tissue or cellular distributions and enzymatic properties, suggesting their distinct biological roles. Although PLA enzymes, particularly cytosolic PLA (cPLAα), have long been implicated in inflammation by driving arachidonic acid metabolism, the precise biological roles of sPLAs have remained a mystery over the last few decades. Recent studies employing mice gene-manipulated for individual sPLAs, in combination with mass spectrometric lipidomics to identify their target substrates and products in vivo, have revealed their roles in diverse biological events, including immunity and associated disorders, through lipid mediator-dependent or -independent processes in given microenvironments. In this review, we summarize our current knowledge of the roles of sPLAs in various immune responses and associated diseases.

Highlights d PLA2G2D is expressed in M2 macrophages in WAT and downregulated in obesity d Global and macrophage-specific PLA2G2D-null mice display increased obesity d PLA2G2D deficiency perturbs adipocyte browning and adaptive thermogenesis d PLA2G2D mobilizes a pool of u3 polyunsaturated fatty acids in WAT

Lipid mediators play pivotal roles in colorectal cancer and colitis, but only a limited member of the phospholipase A2 (PLA2) subtypes, which lie upstream of various lipid mediators, have been implicated in the positive or negative regulation of these diseases. Clinical and biochemical evidence suggests that secreted PLA2 group III (sPLA2-III) is associated with colorectal cancer, although its precise role remains obscure. Here we have found that sPLA2-III-null (Pla2g3 −/−) mice are highly resistant to colon carcinogenesis. Furthermore, Pla2g3 −/− mice are less susceptible to dextran sulfate-induced colitis, implying that the amelioration of colonic inflammation by sPLA2-III ablation may underlie the protective effect against colon cancer. Lipidomics analysis of the colon revealed significant reduction of pro-inflammatory/pro-tumorigenic lysophosholipids as well as unusual steady-state elevation of colon-protective fatty acids and their oxygenated metabolites in Pla2g3 −/− mice. Overall, our results establish a role of sPLA2-III in the promotion of colorectal inflammation and cancer, expand our understanding of the divergent roles of multiple PLA2 enzymes in the gastrointestinal tract, and point to sPLA2-III as a novel druggable target for colorectal diseases.

A B S T R A C TAmong the 11 members of the secreted phospholipase A 2 (sPLA 2 ) family, group IID, IIE, IIF and III sPLA 2 s (sPLA 2 -IID, -IIE, -IIF and -III, respectively) are "new" isoforms in the history of sPLA 2 research. Relative to the better characterized sPLA 2 s (sPLA 2 -IB, -IIA, -V and -X), the enzymatic properties, distributions, and functions of these "new" sPLA 2 s have remained obscure until recently. Our current studies using knockout and transgenic mice for a nearly full set of sPLA 2 s, in combination with comprehensive lipidomics, have revealed unique and distinct roles of these "new" sPLA 2 s in specific biological events. Thus, sPLA 2 -IID is involved in immune suppression, sPLA 2 -IIE in metabolic regulation and hair follicle homeostasis, sPLA 2 -IIF in epidermal hyperplasia, and sPLA 2 -III in male reproduction, anaphylaxis, colonic diseases, and possibly atherosclerosis. In this article, we overview current understanding of the properties and functions of these sPLA 2 s and their underlying lipid pathways in vivo.

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