Novel lipid mediators of innate immunity and inflammation

Abstract

Exposure of human peripheral blood monocytes to free arachidonic acid (AA) results in the rapid induction of lipid droplet (LD) formation by these cells. LD are formed by two different routes, namely (i) the direct entry of AA into triacylglycerol and (ii) activation of intracellular signaling leading to increased neutral lipid formation utilizing fatty acids coming from the de novo biosynthetic route. The latter predominates, accounting for 60-70% of total LD formation, and can be completely inhibited by selective inhibition of the group IVA cytosolic phospholipase A2, pointing out this enzyme as a key regulator of AA-induced signaling. In other work, we applied mass spectrometrybased lipid profiling to study the levels of AA-containing phospholipids in macrophages. We identified an unusual inositol phospholipid molecule, PI(20:4/20:4), the levels of which do not decrease but actually increase by 300% after activation of the cells. Elevating the intracellular concentration of PI(20:4/20:4) by introducing the lipid into the cells results in enhancement of the microbicidal capacity of macrophages but does not change gene expression in response to inflammatory stimuli, highlighting the selectivity of action of PI(20:4/20:4). These findings suggest that PI(20:4/20:4) is a novel bioactive inositol phospholipid molecule that regulates innate immune responses in macrophages.