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PLCG2 regulates endocannabinoid and eicosanoid networks in innate immune cells

ABSTRACT: Human genetic studies have pointed to a prominent role for innate immunity and lipid pathways in human 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 (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 (eCB) 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 eCB-eicosanoid crosstalk 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 pro-inflammatory cytokine 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 crosstalk with endocannabinoid/eicosanoid pathways and modulation of subsets of cellular responses to inflammatory stimuli.

ORGANISM(S): Mus musculus

PROVIDER: GSE180274 | GEO | 2021/10/04

REPOSITORIES: GEO

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Project description:This SuperSeries is composed of the following subset Series:; GSE8290: Comprehensive analysis of PPARÎ±-dependent regulation of hepatic lipid metabolism by expression profiling - 1; GSE8291: Comprehensive analysis of PPARÎ±-dependent regulation of hepatic lipid metabolism by expression profiling - 2; GSE8292: Comprehensive analysis of PPARÎ±-dependent regulation of hepatic lipid metabolism by expression profiling - 3; GSE8295: Comprehensive analysis of PPARÎ±-dependent regulation of hepatic lipid metabolism by expression profiling - 4; GSE8302: Comprehensive analysis of PPARÎ±-dependent regulation of hepatic lipid metabolism by expression profiling - 5; PPARalpha is a ligand-activated transcription factor involved in the regulation of nutrient metabolism and inflammation. Although much is already known about the function of PPARalpha in hepatic lipid metabolism, many PPARalpha-dependent pathways and genes have yet to be discovered. In order to obtain an overview of PPARalpha-regulated genes relevant to lipid metabolism, and to probe for novel candidate PPARalpha target genes, livers from several animal studies in which PPARalpha was activated and/or disabled were analyzed by Affymetrix GeneChips. Numerous novel PPARalpha-regulated genes relevant to lipid metabolism were identified. Out of this set of genes, eight genes were singled out for study of PPARalpha-dependent regulation in mouse liver and in mouse, rat, and human primary hepatocytes, including thioredoxin interacting protein (Txnip), electron-transferring-flavoprotein beta polypeptide (Etfb), electron-transferring-flavoprotein dehydrogenase (Etfdh), phosphatidylcholine transfer protein (Pctp), endothelial lipase (EL, Lipg), adipose triglyceride lipase (Pnpla2), hormone-sensitive lipase (HSL, Lipe), and monoglyceride lipase (Mgll). Using an in silico screening approach, one or more PPAR response elements (PPREs) were identified in each of these genes. Regulation of Pnpla2, Lipe, and Mgll, which are involved in triglyceride hydrolysis, was studied under conditions of elevated hepatic lipids. In wild-type mice fed a high fat diet, the decrease in hepatic lipids following treatment with the PPARalpha agonist Wy14643 was paralleled by significant up-regulation of Pnpla2, Lipe, and Mgll, suggesting that induction of triglyceride hydrolysis may contribute to the anti-steatotic role of PPARalpha. Our study illustrates the power of transcriptional profiling to uncover novel PPARalpha-regulated genes and pathways in liver. Experiment Overall Design: Refer to individual Series

Project description:PPARÎ± is a ligand-activated transcription factor involved in the regulation of nutrient metabolism and inflammation. Although much is already known about the function of PPARÎ± in hepatic lipid metabolism, many PPARÎ±-dependent pathways and genes have yet to be discovered. In order to obtain an overview of PPARÎ±-regulated genes relevant to lipid metabolism, and to probe for novel candidate PPARÎ± target genes, livers from several animal studies in which PPARÎ± was activated and/or disabled were analyzed by Affymetrix GeneChips. Numerous novel PPARÎ±-regulated genes relevant to lipid metabolism were identified. Out of this set of genes, eight genes were singled out for study of PPARÎ±-dependent regulation in mouse liver and in mouse, rat, and human primary hepatocytes, including thioredoxin interacting protein (Txnip), electron-transferring-flavoprotein Î² polypeptide (Etfb), electron-transferring-flavoprotein dehydrogenase (Etfdh), phosphatidylcholine transfer protein (Pctp), endothelial lipase (EL, Lipg), adipose triglyceride lipase (Pnpla2), hormone-sensitive lipase (Lipe), and monoglyceride lipase (Mgll). Using an in silico screening approach, one or more PPAR response elements (PPREs) were identified in each of these genes. Since Pnpla2, Lipe, and Mgll contribute to hepatic triglyceride hydrolysis, gene regulation was studied under conditions of elevated hepatic lipids. In wild-type mice fed a high fat diet, the decrease in hepatic lipids following treatment with the PPARÎ± agonist Wy14643 was paralleled by significant up-regulation of Pnpla2, Lipe, and Mgll, suggesting that induction of triglyceride hydrolysis may contribute to the anti-steatotic role of PPARÎ±. Our study illustrates the power of transcriptional profiling to uncover novel PPARÎ±-regulated genes and pathways in liver. Experiment Overall Design: Primary rat and mouse hepatocytes were incubated in the presence (10 uM) or absence of the synthetic PPARÎ± ligand Wy14643 for 24 hours. Primary human hepatocytes were incubated in the presence (50 uM) or absence of Wy14643 for 12 hours. Total RNA was pooled within groups and hybridized onto Rat Genome 230 2.0 Arrays, Mouse Genome 430 2.0 Arrays or Human Genome U133 Plus 2.0 Arrays.

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PLCG2 regulates endocannabinoid and eicosanoid networks in innate immune cells

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