Deletion of monoglyceride lipase in astrocytes attenuates lipopolysaccharide-induced neuroinflammation

Gernot F. Grabner, Thomas O. Eichmann, Bernhard Wagner, Yuanqing Gao, Aitak Farzi, Ulrike Taschler, Franz P.W. Radner, Martina Schweiger, Achim Lass, Peter Holzer, Erwin Zinser, Matthias H. Tschöp, Chun Xia Yi, Robert Zimmermann

Research output: Contribution to journalArticlepeer-review

52 Scopus citations

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 (MKOGFAP). MKOGFAP mice exhibit moderately increased 2-AG and reduced AA levels in brain. Minor accumulation of 2-AG in the brain of MKOGFAP mice does not cause cannabinoid receptor desensitization as previously observed in mice globally lacking MGL. Importantly, MKOGFAP 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 astrocytespecific 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.

Original languageEnglish
Pages (from-to)913-923
Number of pages11
JournalJournal of Biological Chemistry
Volume291
Issue number2
DOIs
StatePublished - 8 Jan 2016
Externally publishedYes

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