Group X Secreted Phospholipase A2 Releases ω3 Polyunsaturated Fatty Acids, Suppresses Colitis, and Promotes Sperm Fertility

Abstract

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.

The Roles of the Secreted Phospholipase A2 Gene Family in Immunology

“…Contrary to the proposal that PLA2G10 promotes inflammation, PLA2G10-TG mice display striking immunosuppressive and lean phenotypes with lymphopenia and increased M2-like macrophages (Murase et al, 2016). This phenotype is accompanied by marked elevation of antiinflammatory ω3 PUFAs and their metabolites in multiple tissues, indicating for the first time that PLA2G10 has the capacity to release ω3 PUFAs in vivo.…”

“…Hence, even if PLA2G10-transfected cells were capable of releasing AA robustly, this would not necessarily reflect its physiological function. Third, PLA2G10 shows an apparent PUFA preference, releasing ω3 PUFAs such as EPA, DPA, and DHA in addition to, or even preferentially to, ω6 AA from cultured cells, lipoproteins, or even tissues (Murase et al, 2016). However, the ability of PLA2G10 to release ω3 PUFAs in vivo and the resulting pathophysiological outcomes has not been taken into consideration.…”

“…This phenotype is accompanied by marked elevation of antiinflammatory ω3 PUFAs and their metabolites in multiple tissues, indicating for the first time that PLA2G10 has the capacity to release ω3 PUFAs in vivo. In an effort to obtain physiological insight into this phenomenon, studies using Pla2g10 À/À mice have demonstrated that endogenous PLA2G10, which is expressed abundantly in the colon epithelium as a "gastrointestinal sPLA 2 ," mobilizes ω3 PUFAs and their metabolites, rather than ω6 AA metabolites, thereby protecting the tissue from dextran sulfate (DSS)-induced colitis (Murase et al, 2016). Pla2g10 deficiency increases the colorectal expression of Th17 cytokines, and ω3 PUFAs themselves attenuate the production of these cytokines by lamina propria cells from DSS-treated mice, at least in part through the PUFA receptor GPR120.…”

“…With regard to polar head groups, PLA2G2A and other group II sPLA 2 s show preference for phosphatidylethanolamine (PE) over phosphatidylcholine (PC), while PLA2G10 is very active on PC, and these preferences can be partly explained in terms of crystal structure (Pan et al, 2002;Scott et al, 1991). With regard to sn-2 fatty acids, PLA2G1B, PLA2G2A, and PLA2G2E do not distinguish fatty acid species, PLA2G5 prefers fatty acids with a lower degree of unsaturation (eg, oleic acid (OA)), and PLA2G2D, PLA2G2F, PLA2G3, and PLA2G10 show preference for polyunsaturated fatty acids (PUFAs) such as arachidonic acid (AA) and docosahexaenoic acid (DHA) to various degrees (Chen & Dennis, 1998;Chen, Engle, Seilhamer, & Tischfield, 1994b;Cupillard, Koumanov, Mattei, Lazdunski, & Lambeau, 1997;Guillaume et al, 2015;Hanasaki et al, 1999;Miki et al, 2013;Mitsuishi, Masuda, Kudo, & Murakami, 2007;Murakami et al, 2003;Murase et al, 2016;Pruzanski et al, 2005;Sato et al, 2014;Yamamoto et al, 2015). Although the substrate specificity of sPLA 2 s differs according to the in vitro assay conditions employed, particularly when excess amounts of the enzymes are used, the overall tendency is recapitulated in several if not all in vivo systems, often with even more selective patterns of hydrolysis that may be affected by the phospholipid compositions of the target membranes.…”

Expression and Function of Group IIE Phospholipase A2 in Mouse Skin

“…Ideally, sPLA 2 activity should be evaluated with a physiologically relevant membrane on which the enzyme acts intrinsically, as we have recently reported for sPLA 2 -IIF (19). Nonetheless, the overall selectivity of sPLA 2 s for various phospholipid headgroups and fatty acyl chains has been recapitulated by several in vitro enzymatic studies, and the in vivo lipidomics data have revealed even more selective patterns of hydrolysis (19,24,36,37). Although the local concentration of sPLA 2 -IIE in hair follicles is unclear, our present results obtained from the in vitro and in vivo lipidomics approaches have provided a consistent result, implying that the in vitro activity of sPLA 2 -IIE may be physiologically relevant (at least in the skin).…”