Abstract
Glutamate released by activated microglia induces excitoneurotoxicity and may contribute to neuronal damage in neurodegenerative diseases, including Alzheimer disease, Parkinson disease, amyotrophic lateral sclerosis, and multiple sclerosis. In addition, tumor necrosis factor-alpha (TNF-alpha) secreted from activated microglia may elicit neurodegeneration through caspase-dependent cascades and silencing cell survival signals. However, direct neurotoxicity of TNF-alpha is relatively weak, because TNF-alpha also increases production of neuroprotective factors. Accordingly, it is still controversial how TNF-alpha exerts neurotoxicity in neurodegenerative diseases. Here we have shown that TNF-alpha is the key cytokine that stimulates extensive microglial glutamate release in an autocrine manner by up-regulating glutaminase to cause excitoneurotoxicity. Further, we have demonstrated that the connexin 32 hemichannel of the gap junction is another main source of glutamate release from microglia besides glutamate transporters. Although pharmacological blockade of glutamate receptors is a promising therapeutic candidate for neurodegenerative diseases, the associated perturbation of physiological glutamate signals has severe adverse side effects. The unique mechanism of microglial glutamate release that we describe here is another potential therapeutic target. We rescued neuronal cell death in vitro by using a glutaminase inhibitor or hemichannel blockers to diminish microglial glutamate release without perturbing the physiological glutamate level. These drugs may give us a new therapeutic strategy against neurodegenerative diseases with minimum adverse side effects.
Highlights
We demonstrated that activated microglia release large amounts of glutamate and that microglial neurotoxicity is mediated primarily by NMDA3 receptor signaling [13]
We have demonstrated that TNF-␣ is the key cytokine that stimulates extensive microglial glutamate release in an autocrine manner by up-regulating glutaminase to cause excitoneurotoxicity
We examined neuronal damage caused by microglial cytokines by applying the pro-inflammatory cytokines IL-1, IL-6, IFN-␥, and TNF-␣ and anti-inflammatory cytokine IL-10 to neurons or microglia
Summary
We demonstrated that activated microglia release large amounts of glutamate and that microglial neurotoxicity is mediated primarily by NMDA3 receptor signaling [13]. In addition to glutamate, activated microglia release pro-inflammatory cytokines, such as interleukin (IL)-1, IL-6, interferon (IFN)-␥, and tumor necrosis factor-␣ (TNF-␣) (14 –18), which promote neuronal damage. We have demonstrated that TNF-␣ is the key cytokine that stimulates extensive microglial glutamate release in an autocrine manner by up-regulating glutaminase to cause excitoneurotoxicity.
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