Necroptosis mediates TNF-induced toxicity of hippocampal neurons.
Necroptosis mediates TNF-induced toxicity of hippocampal neurons.
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坏死性凋亡介导 TNF 诱导的海马神经元毒性
DOI：
10.1155/2014/290182
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发表时间：
2014
影响因子：
--
通讯作者：
He S
中科院分区：
文献类型：
--
作者：
Liu S;Wang X;Li Y;Xu L;Yu X;Ge L;Li J;Zhu Y;He S
肿瘤坏死因子-α（tumor necrosis factor-α，TNF-α）是调节神经炎症的重要促炎细胞因子。TNF-α水平升高与多种神经退行性疾病相关，如阿尔茨海默病和帕金森病。然而，导致TNF-α引发的神经毒性的信号事件仍然不清楚。在这里，我们报道了RIP 3介导的坏死性凋亡，一种调节性坏死，在侧脑室注射TNF-α后在小鼠海马中被激活。RIP 3缺陷减弱TNF-α引起的海马神经元损失此外，我们还研究了TNF-α诱导HT-22海马神经元细胞毒性的分子机制。HT-22细胞仅在caspase阻断后对TNF-α敏感，随后发生坏死。CYLD或RIP 1或RIP 3或MLKL的敲低抑制细胞死亡，表明这种坏死是坏死性凋亡，并由CYLD-RIP 1-RIP 3-MLKL信号通路介导。TNF-α诱导的HT-22细胞坏死性凋亡在很大程度上独立于活性氧积累和钙内流，尽管这些事件已被证明对某些细胞系的坏死性凋亡至关重要。总之，这些数据不仅提供了RIP 3在TNF-α诱导的海马神经元毒性中的作用的第一个体内证据，而且还证明TNF-α促进CYLD-RIP 1-RIP 3-MLKL介导的海马神经元坏死性凋亡，这在很大程度上绕过了ROS积累和钙内流。
Tumor necrosis factor-α (TNF-α) is a critical proinflammatory cytokine regulating neuroinflammation. Elevated levels of TNF-α have been associated with various neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease. However, the signaling events that lead to TNF-α-initiated neurotoxicity are still unclear. Here, we report that RIP3-mediated necroptosis, a form of regulated necrosis, is activated in the mouse hippocampus after intracerebroventricular injection of TNF-α. RIP3 deficiency attenuates TNF-α-initiated loss of hippocampal neurons. Furthermore, we characterized the molecular mechanism of TNF-α-induced neurotoxicity in HT-22 hippocampal neuronal cells. HT-22 cells are sensitive to TNF-α only upon caspase blockage and subsequently undergo necrosis. The cell death is suppressed by knockdown of CYLD or RIP1 or RIP3 or MLKL, suggesting that this necrosis is necroptosis and mediated by CYLD-RIP1-RIP3-MLKL signaling pathway. TNF-α-induced necroptosis of HT-22 cells is largely independent of both ROS accumulation and calcium influx although these events have been shown to be critical for necroptosis in certain cell lines. Taken together, these data not only provide the first in vivo evidence for a role of RIP3 in TNF-α-induced toxicity of hippocampal neurons, but also demonstrate that TNF-α promotes CYLD-RIP1-RIP3-MLKL-mediated necroptosis of hippocampal neurons largely bypassing ROS accumulation and calcium influx.