Open AccessPhospholipase Cγ2 regulates endocannabinoid and eicosanoid networks in innate immune cells
Author(s) -
Hui Jing,
Alex Reed,
Olesya A. Ulanovskaya,
JanSebastian Grigoleit,
Dylan M. Herbst,
Cassandra Henry,
Haoxin Li,
Sabrina Barbas,
Jason Germain,
Kim Masuda,
Benjamin F. Cravatt
Publication year - 2021
Publication title -
proceedings of the national academy of sciences of the united states of america
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.011
H-Index - 771
eISSN - 1091-6490
pISSN - 0027-8424
DOI - 10.1073/pnas.2112971118
Subject(s) - innate immune system , endocannabinoid system , diacylglycerol lipase , biology , monoacylglycerol lipase , immune system , eicosanoid , microbiology and biotechnology , ccl18 , proinflammatory cytokine , diacylglycerol kinase , immunology , inflammation , signal transduction , receptor , arachidonic acid , biochemistry , protein kinase c , enzyme
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 Cγ2 (PLCγ2 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 PLCγ2, as well as Fc receptor activation in primary human and mouse macrophages. Genetic disruption of PLCγ2 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 PLCγ2 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.