Phospholipase Cγ2 regulates endocannabinoid and eicosanoid networks in innate immune cells

Human genetic studies have pointed to a prominent role for innate immunity and lipid pathways in immunological and neurodegenerative disorders. Our understanding of the composition and function of immunomodulatory lipid networks in innate immune cells, however, remains incomplete. Here, we show that phospholipase C gamma 2 (PLC gamma 2 or PLCG2)-mutations in which are associated with autoinflammatory disorders and Alzheimer's disease-serves as a principal source of diacylglycerol (DAG) pools that are converted into a cascade of bioactive endocannabinoid and eicosanoid lipids by DAG lipase (DAGL) and monoacylglycerol lipase (MGLL) enzymes in innate immune cells. We show that this lipid network is tonically stimulated by disease-relevant human mutations in PLC gamma 2, as well as Fc receptor activation in primary human and mouse macrophages. Genetic disruption of PLC gamma 2 in mouse microglia suppressed DAGL/MGLL-mediated endocannabinoid-eicosanoid cross-talk and also caused widespread transcriptional and proteomic changes, including the reorganization of immune-relevant lipid pathways reflected in reductions in DAGLB and elevations in PLA2G4A. Despite these changes, Plcg2-/- mice showed generally normal proinflammatory cytokine and chemokine responses to lipopolysaccharide treatment, instead displaying a more restricted deficit in microglial activation that included impairments in prostaglandin production and CD68 expression. Our findings enhance the understanding of PLC gamma 2 function in innate immune cells, delineating a role in cross-talk with endocannabinoid/eicosanoid pathways and modulation of subsets of cellular responses to inflammatory stimuli.

Automated summary

Human genetic studies have shown that mutations in PLC gamma 2 are associated with autoinflammatory disorders and Alzheimer's disease, and serve as a principal source of diacylglycerol (DAG) in innate immune cells. These DAG pools are converted into bioactive endocannabinoids and eicosanoids by DAG lipase and monoacylglycerol lipase enzymes. Disruption of PLC gamma 2 in mouse microglia results in impaired endocannabinoid-eicosanoid cross-talk and alterations in immune-relevant lipid pathways.