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Stimulation of microglial metabotropic glutamate receptor mGlu2 triggers tumor necrosis factor alpha-induced neurotoxicity in concert with microglial-derived fas ligand

Taylor, DL; Jones, F; Kubota, ESFCS; Pocock, JM; (2005) Stimulation of microglial metabotropic glutamate receptor mGlu2 triggers tumor necrosis factor alpha-induced neurotoxicity in concert with microglial-derived fas ligand. J NEUROSCI , 25 (11) 2952 - 2964. 10.1523/JNEUROSCI.4456-04.2005. Green open access

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Abstract

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(TNF alpha) 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 TNF alpha release. TNF alpha was only neurotoxic in the presence of microglia or microglial-conditioned medium. The toxicity of TNF alpha 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 TNF alpha 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.

Type: Article
Title: Stimulation of microglial metabotropic glutamate receptor mGlu2 triggers tumor necrosis factor alpha-induced neurotoxicity in concert with microglial-derived fas ligand
Open access status: An open access version is available from UCL Discovery
DOI: 10.1523/JNEUROSCI.4456-04.2005
Keywords: metabotropic glutamate receptor, neurodegenerative disease, microglia, neuroprotection, TNF alpha, FasL, CEREBELLAR GRANULE CELLS, METHYL-D-ASPARTATE, CHROMOGRANIN-A, TNF-ALPHA, INDUCED APOPTOSIS, IN-VITRO, ACTIVATED MICROGLIA, SIGNAL-TRANSDUCTION, ALZHEIMERS-DISEASE, MEDIATED APOPTOSIS
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Neuroinflammation
URI: https://discovery.ucl.ac.uk/id/eprint/7725
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