Stimulation of Microglial Metabotropic Glutamate Receptor mGlu2 Triggers Tumor Necrosis Factor α-Induced Neurotoxicity in Concert with Microglial-Derived Fas Ligand

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,2ЈR,3ЈR-2-(2Ј,3Ј-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-Laspartyl-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-␣ (TNF␣) 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␣ release. TNF␣ was only neurotoxic in the presence of microglia or microglial-conditioned medium. The toxicity of TNF␣ 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␣ 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.

Inflammation, Glutamate, and Glia: A Trio of Trouble in Mood Disorders

“…MGluR2/3/5 is also expressed on microglia with varying modulatory effects. Glutamate binding to microglial mGluR2 promotes neurotoxicity via further release of inflammatory cytokines, glutamate, and nitric oxide (NO), whereas mGluR5 is neuroprotective through the opposing effects on same systems (Piers et al, 2011;Taylor et al, 2005). Considerable recent data implicate TNF in increasing microglial glutamate release.…”

Inflammation‐induced sensitization of the brain in term infants

“…TNFa, TNFb, FasL, TRAIL, and TWEAK). [85][86][87][88][89][90] The interaction of these ligands with their receptors, including TNF receptor 1, FasR, death receptor 4, death receptor 5, and TWEAKR, expressed by oligodendrocyte progenitor cells and neurons, can trigger apoptotic cell death. Death receptor activation triggers an extrinsic pathway of caspase-dependent cell death, or produces truncated Bid, leading to enhancement of Bax-dependent mitochondrial pore formation and cell death.…”

Multiple roles of chemokine CXCL12 in the central nervous system: A migration from immunology to neurobiology

“…At the same time, gp120 or CXCL12 binds microglial CXCR4 to stimulate the production of TNF-α. Interestingly, Taylor DL et al (2005) demonstrated that induction of microglial TNF-α is dependent on the stimulation of mGlu2, which is highly correlated with the microglial neurotoxic phenotype. Further, they found that TNF-α can induce neuronal apoptosis by directly binding to its receptor TNFR1 on the surface of neurons.…”