Phospholipase Cγ2 regulates endocannabinoid and eicosanoid networks in innate immune cells

Abstract

Significance Here, we reveal that activation of phospholipase Cγ2 (PLCγ2) by disease-relevant mutations or Fc receptor signaling stimulates the production of the endocannabinoid 2-arachidonylglycerol and prostaglandins in primary human and mouse immune cells through a pathway that involves the DAG lipase (DAGL) and monoacylglycerol lipase (MGLL) enzymes. Plcg2 deficiency suppressed DAGL/MGLL-mediated endocannabinoid-eicosanoid cross-talk in mouse microglia, leading to impairment in lipopolysaccharide-mediated microglia activation in vivo that included reduced prostaglandin production and CD68 expression. Our studies provide important mechanistic insights into the regulation of lipid signaling pathways in primary immune cells, revealing a PLCγ2-DAGL-MGLL network that may serve as a future target for treating diverse immunopathologies.