Tumor necrosis factor-α induces neurotoxicity via glutamate release from hemichannels of activated microglia in an autocrine manner
Tumor necrosis factor-α induces neurotoxicity via glutamate release from hemichannels of activated microglia in an autocrine manner
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DOI：
10.1074/jbc.m600504200
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发表时间：
2006-07-28
影响因子：
4.8
通讯作者：
Suzumura, Akio
中科院分区：
文献类型：
--
作者：
Takeuchi, Hideyuki;Jin, Shijie;Suzumura, Akio
激活的小胶质细胞释放谷氨酸可诱导激神经毒性，并可能导致神经退行性疾病的神经元损伤，包括阿尔茨海默病、帕金森病、肌萎缩侧索硬化症和多发性硬化症。此外，激活的小胶质细胞分泌的肿瘤坏死因子- α (tnf - α)可能通过caspase依赖性级联反应和沉默细胞存活信号引发神经变性。然而，tnf - α的直接神经毒性相对较弱，因为tnf - α也会增加神经保护因子的产生。因此，tnf - α如何在神经退行性疾病中发挥神经毒性仍存在争议。在这里，我们已经证明tnf - α是通过上调谷氨酰胺酶以自分泌方式刺激小胶质细胞广泛释放谷氨酸的关键细胞因子，从而引起兴奋神经毒性。此外，我们已经证明，除了谷氨酸转运蛋白外，间隙连接的连接蛋白32半通道是小胶质细胞释放谷氨酸的另一个主要来源。虽然谷氨酸受体的药物阻断是神经退行性疾病的一种有希望的治疗候选药物，但相关的生理谷氨酸信号的扰动具有严重的不良副作用。我们在这里描述的小胶质细胞谷氨酸释放的独特机制是另一个潜在的治疗靶点。我们通过谷氨酰胺酶抑制剂或半通道阻滞剂在不干扰生理谷氨酸水平的情况下减少小胶质细胞谷氨酸释放来挽救体外死亡的神经元细胞。这些药物可能为我们提供一种新的治疗神经退行性疾病的策略，并且副作用最小。
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.