Metabotropic glutamate receptor 5 activation inhibits microglial associated inflammation and neurotoxicity.
The Group I metabotropic glutamate receptor 5 (mGluR5) can modulate addiction, pain, and neuronal cell death. Expression of some mGluRs, such as Group II and III mGluRs, has been reported in microglia and may affect their activation. However, the expression and role of mGluR5 in microglia is unclear. Using immunocytochemistry and Western blot, we demonstrate that mGluR5 protein is expressed in primary microglial cultures. Activation of mGluR5 using the selective agonist (RS)-2-chloro-5-hydroxyphenylglycine (CHPG) significantly reduces microglial activation in response to lipopolysaccharide, as indicated by a reduction in nitric oxide, reactive oxygen species, and TNFalpha production. Microglial induced neurotoxicity is also markedly reduced by CHPG treatment. The anti-inflammatory effects of CHPG are not observed in microglial cultures from mGluR5 knockout mice and are blocked by selective mGluR5 antagonists, suggesting that these actions are mediated by the mGluR5 receptor. Anti-inflammatory actions of mGluR5 activation are attenuated by phospholipase C and protein kinase C inhibitors, as well as by calcium chelators, suggesting that the mGluR5 activation in microglia involves the G(alphaq)-protein signal transduction pathway. These data indicate that microglial mGluR5 may represent a novel target for modulating neuroinflammation, an important component of both acute and chronic neurodegenerative disorders.
Byrnes
Kimberly R
KR
Department of Neuroscience, Georgetown University Medical Center, 3970 Reservoir Road N.W., Washington, DC 20057, USA. krb27@georgetown.edu
Stoica
Bogdan
B
Loane
David J
DJ
Riccio
Angela
A
Davis
Margaret I
MI
Faden
Alan I
AI
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D002118:Calcium; D002478:Cells, Cultured; D002614:Chelating Agents / Q000494:pharmacology; D018683:Excitatory Amino Acid Agents / Q000494:pharmacology; D005998:Glycine / Q000031:analogs & derivatives / Q000494:pharmacology; D007249:Inflammation / Q000503:physiopathology*; D008070:Lipopolysaccharides / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017628:Microglia / Q000502:physiology*; D009474:Neurons / Q000502:physiology*; D018696:Neuroprotective Agents / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism; D010648:Phenylacetates / Q000494:pharmacology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D010738:Type C Phospholipases / Q000378:metabolism
C107349:2-chloro-5-hydroxyphenylglycine; D000893:Anti-Inflammatory Agents; D002614:Chelating Agents; D018683:Excitatory Amino Acid Agents; C578936:Grm5 protein, mouse; C578937:Grm5 protein, rat; D008070:Lipopolysaccharides; D018696:Neuroprotective Agents; D010648:Phenylacetates; D017382:Reactive Oxygen Species; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate; D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide; D011493:Protein Kinase C; D010738:Type C Phospholipases; D002118:Calcium; D005998:Glycine