Segregated functions of two cytosolic phospholipase A₂ isoforms (cPLA₂α and cPLA₂ε) in lipid mediator generation

Among the phospholipase A₂ (PLA₂) superfamily, group IVA cytosolic PLA₂ (cPLA₂α) is currently attracting much attention as a central regulator of arachidonic acid (AA) metabolism linked to eicosanoid biosynthesis. Following cell activation, cPLA₂α selectively releases AA, a precursor of a variety of eicosanoids, from phospholipids in perinuclear membrane compartments. cPLA₂α-null mice display various phenotypes that could be largely explained by reduced eicosanoid signaling. In contrast, group IVE cPLA₂ε, another member of the cPLA₂ family, acts as a Ca²⁺-dependent N-acyltransferase rather than a PLA₂, thereby regulating the biosynthesis of N-acylethanolamines (NAEs), a unique class of lipid mediators with an anti-inflammatory effect. In response to Ca²⁺ signaling, cPLA₂ε translocates to phosphatidylserine-rich organelle membranes in the endocytic/recycling pathway. In vivo, cPLA₂ε is induced in keratinocytes of psoriatic skin, and its genetic deletion exacerbates psoriatic inflammation due to a marked reduction of NAE-related lipids. cPLA₂ε also contributes to NAE generation in several if not all mouse tissues. Thus, the two members of the cPLA₂ family, cPLA₂α and cPLA₂ε, catalyze distinct enzymatic reactions to mobilize distinct sets of lipid mediators, thereby differently regulating pathophysiological events in health and disease. Such segregation of the cPLA₂α-eicosanoid and cPLA₂ε-NAE pathways represents a new paradigm of research on PLA₂s and lipid mediators.