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Phospholipase Cγ2 regulates endocannabinoid and eicosanoid networks in innate immune cells

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Jing, Hui, Reed, Alex, Ulanovskaya, Olesya A., Grigoleit, Jan-Sebastian, Herbst, Dylan M., Henry, Cassandra L., Li, Haoxin, Barbas, Sabrina +3 more·2021·Proceedings of the National Academy of Sciences
DOI 10.1073/pnas.2112971118PMC PMC8522274
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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.

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  • Other more strongly hypermorphic PLCG2 variants are associated with APLAID, while other loss-of-function PLCG2 variants are associated with CVID and PLAID.

    “Other more strongly hypermorphic PLCG2 variants are associated with autoimmune PLCγ2-associated antibody deficiency and immune dysregulation (APLAID) (15), while other loss-of-function PLCG2 variants are associated with common variable immunodeficiency (CVID) and PLAID (18).”

    From Multi-omics analyses reveal novel effects of PLCγ2 deficiency in the mouse brain (2023) · cites this paper as [15]

    The source’s Abstract (page unavailable) links germline PLCG2 exon deletions to PLAID, supporting that disease association. It does not identify those variants as loss-of-function or link PLCG2 variants to CVID. The APLAID clause carries a different citation, so it is not the basis of this verdict. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • A previous study examining microglia gene expression from Plcg2 KO mice also found rewiring of PIP2 and DAG metabolism, with decreases in DGKE and DAGL which both degrade DAG and increases in PLA2G4A which shunts PI away from production of PIP2 to generate free fatty acids such as arachidonic acid.

    “A previous study examining microglia gene expression from Plcg2 KO mice also found rewiring of PIP2 and DAG metabolism, with decreases in DGKE and DAGL which both degrade DAG and increases in PLA2G4A which shunts PI away from production of PIP2 to generate free fatty acids such as arachidonic acid (15).”

    From Multi-omics analyses reveal novel effects of PLCγ2 deficiency in the mouse brain (2023) · cites this paper as [15]

    Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

    Experimental — accuracy not yet measured

  • In alignment with our data, this study also found reduced production of DAG in microglia isolated from Plcg2 KO mice.

    “In alignment with our data, this study also found reduced production of DAG in microglia isolated from Plcg2 KO mice (15).”

    From Multi-omics analyses reveal novel effects of PLCγ2 deficiency in the mouse brain (2023) · cites this paper as [15]

    The Results (page unavailable; Fig. 4D) report that IgG-IC treatment increased SAG, a DAG species, in wild-type microglia but not in Plcg2 knockout microglia. This supports reduced stimulus-induced DAG-pathway activity, but the paper does not establish a general reduction in DAG production in the knockout microglia without that stimulus qualifier. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

  • In microglia, PLCγ2 activity is downstream of TREM2 and Fc receptors, regulating inflammatory processes, migration, and endocytosis.

    “In microglia PLCγ2 activity has been documented to be downstream of TREM2 (19) and Fc receptors (15), regulating inflammatory processes, migration, and endocytosis (13, 16, 25, 33, 34).”

    From Multi-omics analyses reveal novel effects of PLCγ2 deficiency in the mouse brain (2023) · cites this paper as [15]

    The Results report that PLCγ2 loss impairs prostaglandin production and microglial activation in response to inflammatory stimuli, with a possible effect on phagocytosis. The Discussion also describes PLCγ2 as signaling downstream of TREM2 in microglia. Our copy does not establish a role in microglial migration or endocytosis; its endocytosis mention is in the title of a referenced study. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • The PLCγ2 P522R protective variant is a functional hypermorph.

    “The phospholipase C-γ−2 (PLCγ2) P522R protective variant is a functional hypermorph (12–16), while it is predicted that M28L is a loss-of-function variant (17).”

    From Multi-omics analyses reveal novel effects of PLCγ2 deficiency in the mouse brain (2023) · cites this paper as [15]

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Authors
Jing, H., Reed, A., Ulanovskaya, O. A., Grigoleit, J.-S., Herbst, D. M., Henry, C. L., Li, H., Barbas, S., Germain, J., Masuda, K., & Cravatt, B. F.
Affiliations
  • Scripps Research Institute (US)
  • Lundbeck La Jolla Research Center, La Jolla, CA 92121
ORCID
Venue
Proceedings of the National Academy of Sciences
Publisher
National Academy of Sciences
Published
2021-10-04
Volume
118
Issue
41
ISSN
  • 0027-8424 (ISSN-L)
  • 1091-6490
DOI
10.1073/pnas.2112971118
PMC
PMC8522274
OpenAlex
W3202846314
Cited by
24
References
24
Citations by year
2026: 1 · 2025: 5 · 2024: 7 · 2023: 6 · 2022: 4 · 2021: 1
FWCI
2.62
Type
journal article
Language
en
Open access
Licence
www.pnas.org/site/aboutpnas/licenses.xhtml (vor, 182 d)
Locations
  • Proceedings of the National Academy of Sciences (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
HHS | NIH | National Institute on Drug Abuse (DA037660)
Topics
  • Health Sciences › Medicine › Pharmacology › Cannabis and Cannabinoid Research
  • Health Sciences › Nursing › Nutrition and Dietetics › Fatty Acid Research and Health
  • Health Sciences › Medicine › Pharmacology › Inflammatory mediators and NSAID effects
Keywords
PLCγ2, endocannabinoid system, eicosanoids, 2-arachidonoylglycerol, prostaglandins, monoacylglycerol lipase, Fc receptor signaling, microglial activation, lipopolysaccharide, lipid signaling, innate immunity, CD68
MeSH terms
CD68 Molecule, Animals, Cell Line, Chlorocebus aethiops, Diglycerides, Humans, Immunity, Innate, Inflammation, Lipopolysaccharides, Lipoprotein Lipase, Macrophages, Mice, Inbred C57BL, Monoacylglycerol Lipases, Prostaglandins, Receptors, Fc, Antigens, Differentiation, Myelomonocytic, Signal Transduction, Antigens, CD, Eicosanoids, Cytokines, Microglia, Mice, Knockout, COS Cells, Mice, Phospholipase C gamma, Group IV Phospholipases A2, HEK293 Cells, Endocannabinoids

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