Stimulation of microglial metabotropic glutamate receptor mGlu2 triggers tumor necrosis factor alpha-induced neurotoxicity in concert with microglial-derived Fas ligand.
Activated microglia may be detrimental to neuronal survival in a number of neurodegenerative diseases. Thus, strategies that reduce microglial neurotoxicity may have therapeutic benefit. Stimulation of group II metabotropic glutamate (mGlu) receptors on rat primary microglia with the specific group II agonist 2S,2'R,3'R-2-(2',3'-dicarboxy-cyclopropyl)glycine for 24 h induced microglial activation and resulted in a neurotoxic microglial phenotype. These effects were attributable to preferential mGlu2 stimulation, because N-acetyl-L-aspartyl-L-glutamate, a specific mGlu3 agonist, did not induce microglial activation or neurotoxicity. Stimulation of microglial mGlu2 but not mGlu3 induced caspase-3 activation in cerebellar granule neurons in culture, using microglial-conditioned media as well as cocultures. Stimulation of microglial mGlu2 induced tumor necrosis factor-alpha (TNFalpha) release, which contributed to microglial neurotoxicity mediated via neuronal TNF receptor 1 and caspase-3 activation. Stimulation of microglial group I or III mGlu receptors did not induce TNFalpha release. TNFalpha was only neurotoxic in the presence of microglia or microglial-conditioned medium. The toxicity of TNFalpha could be prevented by coexposure of neurons to conditioned medium from microglia stimulated by the specific group III agonist L-2-amino-4-phosphono-butyric acid. The neurotoxicity of TNFalpha derived from mGlu2-stimulated microglia was potentiated by microglial-derived Fas ligand (FasL), the death receptor ligand. FasL was constitutively expressed in microglia and shed after mGlu2 stimulation. Our data suggest that selective and inverse modulation of microglial mGlu2 and mGlu3 may prove a therapeutic target in neuroinflammatory diseases such as Alzheimer's disease and multiple sclerosis.
Taylor
Deanna L
DL
Cell Signalling Laboratory, Department of Neuroinflammation, Institute of Neurology, University College London, London WC1N 1PJ, United Kingdom.
Jones
Fleur
F
Kubota
Eva S F Chen Seho
ES
Pocock
Jennifer M
JM
D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D002452:Cell Count / Q000379:methods; D002478:Cells, Cultured; D002531:Cerebellum / Q000166:cytology; D018920:Coculture Techniques / Q000379:methods; D017077:Culture Media, Conditioned / Q000494:pharmacology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D053331:Ectodysplasins; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D053222:Fas Ligand Protein; D015870:Gene Expression / Q000187:drug effects; D008070:Lipopolysaccharides / Q000494:pharmacology; D008562:Membrane Glycoproteins / Q000633:toxicity*; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D017628:Microglia / Q000187:drug effects / Q000378:metabolism*; D008928:Mitochondria / Q000187:drug effects; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D020258:Neurotoxicity Syndromes / Q000209:etiology / Q000378:metabolism / Q000503:physiopathology; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D018094:Receptors, Metabotropic Glutamate / Q000378:metabolism*; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000378:metabolism; D047889:Receptors, Tumor Necrosis Factor, Type II / Q000378:metabolism; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism / Q000633:toxicity*; D048069:Tumor Necrosis Factors / Q000378:metabolism / Q000633:toxicity*
D017077:Culture Media, Conditioned; D053331:Ectodysplasins; C506019:Eda protein, mouse; D018691:Excitatory Amino Acid Antagonists; D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; C505662:Faslg protein, rat; D008070:Lipopolysaccharides; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D018094:Receptors, Metabotropic Glutamate; D047888:Receptors, Tumor Necrosis Factor, Type I; D047889:Receptors, Tumor Necrosis Factor, Type II; D014409:Tumor Necrosis Factor-alpha; D048069:Tumor Necrosis Factors; C108822:metabotropic glutamate receptor 2; D052247:Nitric Oxide Synthase Type II; C505409:Casp3 protein, mouse; C505410:Casp3 protein, rat; D053148:Caspase 3; D020169:Caspases