Novel lipid mediators of innate immunity and inflammation

Abstract

Phospholipase A2s generate lipid mediators that constitute an important component of the integrated response of macrophages to stimuli of the innate immune response. Because these cells contain multiple phospholipase A2 forms, the challenge is to elucidate the roles that each of these forms plays in regulating normal cellular processes and in disease pathogenesis. A major issue is to precisely determine the phospholipid substrates that these enzymes use for generating lipid mediators. There is compelling evidence that group IVA cytosolic phospholipase A2 (cPLA2α) targets arachidonic acid-containing phospholipids but the role of the other cytosolic enzyme present in macrophages, the Ca2+-independent group VIA phospholipase A2 (iPLA2β) has not been clearly defined. We applied mass spectrometry¿based lipid profiling to study the substrate specificities of these two enzymes during inflammatory activation of macrophages with yeast-derived zymosan, a phagocytosable particle. Using selective inhibitors, we find that, contrary to cPLA2α, iPLA2β spares arachidonate-containing phospholipids and hydrolyzes only those that do not contain arachidonate, in particular choline phospholipids containing palmitic acid at the sn-1 position. This in turn results in the liberation of palmitoleic acid, which is incorporated into inositol lipids. The biological significance of this novel iPLA2β-driven pathway will be discussed.