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J Biol Chem. 2016 Jan 8;291(2):913-23. doi: 10.1074/jbc.M115.683615. Epub 2015 Nov 12.

Deletion of Monoglyceride Lipase in Astrocytes Attenuates Lipopolysaccharide-induced Neuroinflammation.

Author information

1
From the Institute of Molecular Biosciences, University of Graz, 8010 Graz, Austria.
2
the Institute of Biomedical Science, FH Joanneum University of Applied Sciences, 8020 Graz, Austria.
3
the Institute of Diabetes and Obesity, Helmholtz Center Munich, 85748 Garching, Germany.
4
the Institute of Experimental and Clinical Pharmacology, Medical University of Graz, 8010 Graz, Austria, and.
5
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.
6
From the Institute of Molecular Biosciences, University of Graz, 8010 Graz, Austria, robert.zimmermann@uni-graz.at.

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.

KEYWORDS:

arachidonic acid (AA) (ARA); astrocyte; endocannabinoid; lipopolysaccharide (LPS); neuroinflammation

PMID:
26565024
PMCID:
PMC4705409
DOI:
10.1074/jbc.M115.683615
[Indexed for MEDLINE]
Free PMC Article

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