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J. Biol. Chem., Vol. 281, Issue 30, 21362-21368, July 28, 2006
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Tumor Necrosis Factor-
Induces Neurotoxicity via Glutamate Release from Hemichannels of Activated Microglia in an Autocrine Manner*
From the Department of Neuroimmunology, Research Institute of Environmental Medicine, Nagoya University, Furo-cho, Chikusa-ku, Nagoya 464-8601, Japan
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-
(TNF-) secreted from activated microglia may elicit neurodegeneration through caspase-dependent cascades and silencing cell survival signals. However, direct neurotoxicity of TNF- is relatively weak, because TNF- also increases production of neuroprotective factors. Accordingly, it is still controversial how TNF- exerts neurotoxicity in neurodegenerative diseases. Here we have shown that TNF- 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.
Received for publication, January 18, 2006 , and in revised form, April 7, 2006.
* This work was supported by grants from the Ministry of Health, Labor, and Welfare of Japan, a grant-in-aid for young scientists, and a grant-in-aid for 21st Century Center of Excellence Program from the Ministry of Education, Culture, Sports, Science, and Technology of Japan. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 These authors contributed equally to this work.
2 To whom correspondence should be addressed: Dept. of Neuroimmunology, Research Institute of Environmental Medicine, Nagoya University, Furo-cho, Chikusa-ku, Nagoya, 464-8601 Japan. Tel.: +81-52-789-3883; Fax: +81-52-789-5047; E-mail: htake{at}riem.nagoya-u.ac.jp.
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