A new era of secreted phospholipase A₂

Abstract

Among more than 30 members of the phospholipase A2 (PLA2) superfamily, secreted PLA2 (sPLA2) enzymes represent the largest family, being Ca(2+)-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 noncellular 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.

Keywords: arachidonic acid; eicosanoids; fatty acid; immunology; inflammation; lipidomics; lysophospholipid; membranes; obesity; phospholipids/metabolism.

Fig. 1.

A phylogenetic tree of the sPLA₂ family and the functions of individual sPLA₂s as revealed by studies using gene-manipulated mice. Several examples for the functions of individual sPLA₂s, in which underlying lipid metabolisms have been clarified (see text), are illustrated on the phylogenetic tree. The overall functions of sPLA₂s reported so far are summarized in Table 1. Although sPLA₂-XIIB, which is catalytically inactive, has been implicated in steatohepatitis, the mechanistic action is unknown.

Fig. 2.

Examples of the sPLA₂-driven lipid pathways. Individual sPLA₂s are involved in distinct biological processes or diseases through driving unique lipid pathways that involve or do not depend on lipid mediators. In all cases, sPLA₂s act on extracellular phospholipids (e.g., adjacent cells, lipoproteins, microparticles, diet, and bacteria membranes) after secretion. For details, please see the text. RvD1, resolvin D1; OA, oleic acid; LA, linoleic acid.