Title : Deletion of Monoglyceride Lipase in Astrocytes Attenuates Lipopolysaccharide-induced Neuroinflammation - Grabner_2016_J.Biol.Chem_291_913 |
Author(s) : Grabner GF , Eichmann TO , Wagner B , Gao Y , Farzi A , Taschler U , Radner FP , Schweiger M , Lass A , Holzer P , Zinser E , Tschop MH , Yi CX , Zimmermann R |
Ref : Journal of Biological Chemistry , 291 :913 , 2016 |
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. |
PubMedSearch : Grabner_2016_J.Biol.Chem_291_913 |
PubMedID: 26565024 |
Grabner GF, Eichmann TO, Wagner B, Gao Y, Farzi A, Taschler U, Radner FP, Schweiger M, Lass A, Holzer P, Zinser E, Tschop MH, Yi CX, Zimmermann R (2016)
Deletion of Monoglyceride Lipase in Astrocytes Attenuates Lipopolysaccharide-induced Neuroinflammation
Journal of Biological Chemistry
291 :913
Grabner GF, Eichmann TO, Wagner B, Gao Y, Farzi A, Taschler U, Radner FP, Schweiger M, Lass A, Holzer P, Zinser E, Tschop MH, Yi CX, Zimmermann R (2016)
Journal of Biological Chemistry
291 :913