Fatty acid chain length drives lysophosphatidylserine-dependent immunological outputs

Abstract

Lysophosphatidylserines (Lyso-PSs) are potent lipid regulators of important immunological processes. Given their structural diversity and commercial paucity, here, we report the synthesis of a library of methyl-esters of lyso-PS, containing medium to very-long chain (VLC) lipid tails. We assay these lipids against ABHD12, deleterious mutations of which cause a human neurological disorder, and confirm this enzyme’s preference for VLC lysoPSs. Next, we demonstrate that VLC lyso-PSs orchestrate pro-inflammatory responses via a Toll-like receptor 2 dependent pathway, while long chain (LC) lyso-PSs signal through a putative G-Protein Coupled Receptor to influence macrophage activation. We also report that LC lyso-PSs best induce histamine release during mast cell degranulation, and that ABHD12 is a major lyso-PS lipase in these immune cells. Our findings thus illuminate a physiological balance between LC and VLC lyso-PSs, intricately regulated by ABHD12, and disrupting this fine-tuned homeostasis results in immunological outputs, that have detrimental pathological consequences in humans.