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Grabner, G.F.* ; Eichmann, T.O.* ; Wagner, B.* ; Gao, Y. ; Farzi, A.* ; Taschler, U.* ; Radner, F.P.* ; Schweiger, M.* ; Lass, A.* ; Holzer, P.* ; Zinser, E.* ; Tschöp, M.H. ; Yi, C.-X. ; Zimmermann, R.*

Deletion of monoglyceride lpase in astrocytes attenuates lipopolysaccharide-induced neuroinflammation.

J. Biol. Chem. 291, 913-923 (2016)
Verlagsversion Postprint DOI
Open Access Green
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 cytokines 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.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter Arachidonic Acid (aa) (ara) ; Astrocyte ; Endocannabinoid ; Lipopolysaccharide (lps) ; Neuroinflammation
ISSN (print) / ISBN 0021-9258
e-ISSN 1083-351X
Quellenangaben Band: 291, Heft: 2, Seiten: 913-923 Artikelnummer: , Supplement: ,
Verlag American Society for Biochemistry and Molecular Biology
Begutachtungsstatus Peer reviewed