title: Deletion of Monoglyceride Lipase in Astrocytes Attenuates Lipopolysaccharide-induced Neuroinflammation.
abstract: Monoglyceride lipase (MGL) is required for efficient hydrolysis of the endocannabinoid 2-arachidonoylglyerol (2-AG) in the brain generating arachidonic acid (AA) and glycerol. This metabolic function makes MGL an interesting target for the treatment of neuroinflammation, since 2-AG exhibits anti-inflammatory properties and AA is a precursor for pro-inflammatory prostaglandins. Astrocytes are an important source of AA and 2-AG, and highly express MGL. In the present study, we dissected the distinct contribution of MGL in astrocytes on brain 2-AG and AA metabolism by generating a mouse model with genetic deletion of MGL specifically in astrocytes (MKO(GFAP)). MKO(GFAP) mice exhibit moderately increased 2-AG and reduced AA levels in brain. Minor accumulation of 2-AG in the brain of MKO(GFAP) mice does not cause cannabinoid receptor desensitization as previously observed in mice globally lacking MGL. Importantly, MKO(GFAP) mice exhibit reduced brain prostaglandin E2 and pro-inflammatory cytokine levels upon peripheral lipopolysaccharide (LPS) administration. These observations indicate that MGL-mediated degradation of 2-AG in astrocytes provides AA for prostaglandin synthesis promoting LPS-induced neuroinflammation. The beneficial effect of astrocyte-specific MGL-deficiency is not fully abrogated by the inverse cannabinoid receptor 1 agonist SR141716 (Rimonabant) suggesting that the anti-inflammatory effects are rather caused by reduced prostaglandin synthesis than by activation of cannabinoid receptors. In conclusion, our data demonstrate that MGL in astrocytes is an important regulator of 2-AG levels, AA availability, and neuroinflammation.
authors.affiliation: From the Institute of Molecular Biosciences, University of Graz, 8010 Graz, Austria.
authors.forename: Gernot F
authors.initials: GF
authors.lastname: Grabner
authors.affiliation: From the Institute of Molecular Biosciences, University of Graz, 8010 Graz, Austria.
authors.forename: Thomas O
authors.initials: TO
authors.lastname: Eichmann
authors.affiliation: the Institute of Biomedical Science, FH Joanneum University of Applied Sciences, 8020 Graz, Austria.
authors.forename: Bernhard
authors.initials: B
authors.lastname: Wagner
authors.affiliation: the Institute of Diabetes and Obesity, Helmholtz Center Munich, 85748 Garching, Germany.
authors.forename: Yuanqing
authors.initials: Y
authors.lastname: Gao
authors.affiliation: the Institute of Experimental and Clinical Pharmacology, Medical University of Graz, 8010 Graz, Austria, and.
authors.forename: Aitak
authors.initials: A
authors.lastname: Farzi
authors.affiliation: From the Institute of Molecular Biosciences, University of Graz, 8010 Graz, Austria.
authors.forename: Ulrike
authors.initials: U
authors.lastname: Taschler
authors.affiliation: From the Institute of Molecular Biosciences, University of Graz, 8010 Graz, Austria.
authors.forename: Franz P W
authors.initials: FP
authors.lastname: Radner
authors.affiliation: From the Institute of Molecular Biosciences, University of Graz, 8010 Graz, Austria.
authors.forename: Martina
authors.initials: M
authors.lastname: Schweiger
authors.affiliation: From the Institute of Molecular Biosciences, University of Graz, 8010 Graz, Austria.
authors.forename: Achim
authors.initials: A
authors.lastname: Lass
authors.affiliation: the Institute of Experimental and Clinical Pharmacology, Medical University of Graz, 8010 Graz, Austria, and.
authors.forename: Peter
authors.initials: P
authors.lastname: Holzer
authors.affiliation: the Institute of Biomedical Science, FH Joanneum University of Applied Sciences, 8020 Graz, Austria.
authors.forename: Erwin
authors.initials: E
authors.lastname: Zinser
authors.affiliation: the Institute of Diabetes and Obesity, Helmholtz Center Munich, 85748 Garching, Germany.
authors.forename: Matthias H
authors.initials: MH
authors.lastname: Tschöp
authors.affiliation: the Institute of Diabetes and Obesity, Helmholtz Center Munich, 85748 Garching, Germany, the Department of Endocrinology and Metabolism, Academic Medical Center Amsterdam, 1105 Amsterdam, The Netherlands.
authors.forename: Chun-Xia
authors.initials: CX
authors.lastname: Yi
authors.affiliation: From the Institute of Molecular Biosciences, University of Graz, 8010 Graz, Austria, robert.zimmermann@uni-graz.at.
authors.forename: Robert
authors.initials: R
authors.lastname: Zimmermann
mesh_terms: D000818:Animals; D001095:Arachidonic Acids / Q000378:metabolism; D001253:Astrocytes / Q000201:enzymology* / Q000473:pathology; D001522:Behavior, Animal; D001921:Brain / Q000201:enzymology; D016207:Cytokines / Q000378:metabolism; D063388:Endocannabinoids / Q000378:metabolism; D005260:Female; D017353:Gene Deletion; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D005989:Glycerides / Q000378:metabolism; D007249:Inflammation / Q000201:enzymology* / Q000473:pathology*; D008070:Lipopolysaccharides; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017628:Microglia / Q000378:metabolism / Q000473:pathology; D008994:Monoacylglycerol Lipases / Q000378:metabolism*; D009420:Nervous System / Q000201:enzymology* / Q000473:pathology*; D009928:Organ Specificity; D043884:Receptor, Cannabinoid, CB1 / Q000378:metabolism
chemical_list: D001095:Arachidonic Acids; D016207:Cytokines; D063388:Endocannabinoids; D005904:Glial Fibrillary Acidic Protein; D005989:Glycerides; D008070:Lipopolysaccharides; D043884:Receptor, Cannabinoid, CB1; C094503:glyceryl 2-arachidonate; D008994:Monoacylglycerol Lipases
keywords: arachidonic acid (AA) (ARA); astrocyte; endocannabinoid; lipopolysaccharide (LPS); neuroinflammation