biostudies-literatureJing HHHS | NIH | National Institute on Drug Abusee2112971118https://www.ebi.ac.uk/biostudies/studies/S-EPMC8522274biostudies-literatureUnknown118(41)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 priProceedings of the National Academy of Sciences of the United States of AmericaPhospholipase Cγ2 regulates endocannabinoid and eicosanoid networks in innate immune cells.PMC8522274DA037660Jing HGrigoleit JSLi HBarbas SCravatt BFGermain JHerbst DMUlanovskaya OAHenry CLMasuda KReed AfalsePhospholipase 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 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 pri2021-01-01T00:00:00Z2021 Oct2025-04-05T14:05:11.547Z2025-04-05T14:05:11.547ZS-EPMC85222743460796010.1073/pnas.2112971118