Among more than 30 members of the phospholipase A2 (PLA2) superfamily, secreted PLA2 (sPLA2) enzymes represent the largest family, being Ca2+-dependent low-molecular-weight enzymes with a His-Asp catalytic dyad. Individual sPLA2s exhibit unique tissue and cellular distributions and enzymatic properties, suggesting their distinct biological roles. Recent studies using transgenic and knockout mice for nearly a full set of sPLA2 subtypes, in combination with sophisticated lipidomics as well as biochemical and cell biological studies, have revealed distinct contributions of individual sPLA2s to various pathophysiological events, including production of pro- and anti-inflammatory lipid mediators, regulation of membrane remodeling, degradation of foreign phospholipids in microbes or food, or modification of extracellular non-cellular lipid components. In this review, we highlight the current understanding of the in vivo functions of sPLA2s and the underlying lipid pathways as revealed by a series of studies over the last decade.

Phospholipase A₂ (PLA₂) catalyses the hydrolysis of the sn-2 position of glycerophospholipids to yield fatty acids and lysophospholipids. So far, more than 30 enzymes that possess PLA₂ or related activity have been identified in mammals. About one third of these enzymes belong to the secreted PLA₂ (sPLA₂) family, which comprises low molecular weight, Ca²⁺ requiring, secreted enzymes with a His/Asp catalytic dyad. Individual sPLA₂s display distinct localizations and enzymatic properties, suggesting their specialized biological roles. However, in contrast to intracellular PLA₂s, whose roles in signal transduction and membrane homoeostasis have been well documented, the biological roles of sPLA₂s in vivo have remained obscure until recently. Over the past decade, information fuelled by studies employing knockout and transgenic mice as well as specific inhibitors, in combination with lipidomics, has clarified when and where the different sPLA₂ isoforms are expressed, which isoforms are involved in what types of pathophysiology, and how they exhibit their specific functions. In this review, we highlight recent advances in PLA₂ research, focusing mainly on the physiological functions of sPLA₂s and their modes of action on ‘extracellular’ phospholipid targets versus lipid mediator production.

The phospholipase A₂ (PLA₂) superfamily contains more than 50 enzymes in mammals that are subdivided into several distinct families on a structural and biochemical basis. In principle, PLA₂ has the capacity to hydrolyze the sn-2 position of glycerophospholipids to release fatty acids and lysophospholipids, yet several enzymes in this superfamily catalyze other reactions rather than or in addition to the PLA₂ reaction. PLA₂ enzymes play crucial roles in not only the production of lipid mediators, but also membrane remodeling, bioenergetics, and body surface barrier, thereby participating in a number of biological events. Accordingly, disturbance of PLA₂-regulated lipid metabolism is often associated with various diseases. This review updates the current state of understanding of the classification, enzymatic properties, and biological functions of various enzymes belonging to the PLA₂ superfamily, focusing particularly on the novel roles of PLA₂s in vivo.

Resolution of inflammation is an active process that is mediated in part by antiinflammatory lipid mediators. Although phospholipase A₂ (PLA₂) enzymes have been implicated in the promotion of inflammation through mobilizing lipid mediators, the molecular entity of PLA₂ subtypes acting upstream of antiinflammatory lipid mediators remains unknown. Herein, we show that secreted PLA₂ group IID (PLA2G2D) is preferentially expressed in CD11c⁺ dendritic cells (DCs) and macrophages and displays a pro-resolving function. In hapten-induced contact dermatitis, resolution, not propagation, of inflammation was compromised in skin and LNs of PLA2G2D-deficient mice (Pla2g2d^−/−), in which the immune balance was shifted toward a proinflammatory state over an antiinflammatory state. Bone marrow-derived DCs from Pla2g2d^−/− mice were hyperactivated and elicited skin inflammation after intravenous transfer into mice. Lipidomics analysis revealed that PLA2G2D in the LNs contributed to mobilization of a pool of polyunsaturated fatty acids that could serve as precursors for antiinflammatory/pro-resolving lipid mediators such as resolvin D1 and 15-deoxy-Δ^12,14-prostaglandin J₂, which reduced Th1 cytokine production and surface MHC class II expression in LN cells or DCs. Altogether, our results highlight PLA2G2D as a “resolving sPLA₂” that ameliorates inflammation through mobilizing pro-resolving lipid mediators and points to a potential use of this enzyme for treatment of inflammatory disorders.