Segregated functions of two cytosolic phospholipase A isoforms (cPLAα and cPLAε) in lipid mediator generation.

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