Tumor necrosis factor receptor 1 is a negative regulator of progenitor proliferation in adult hippocampal neurogenesis
Tumor necrosis factor receptor 1 is a negative regulator of progenitor proliferation in adult hippocampal neurogenesis
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DOI：
10.1523/jneurosci.2723-06.2006
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发表时间：
2006-09-20
影响因子：
5.3
通讯作者：
Lindvall, Olle
中科院分区：
文献类型：
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作者：
Iosif, Robert E.;Ekdahl, Christine T.;Lindvall, Olle
肿瘤坏死因子-α是一种促炎细胞因子，通过肿瘤坏死因子-R1和肿瘤坏死因子-R2受体发挥作用。这两种受体被认为在中枢神经系统中介导不同的肿瘤坏死因子-α效应，其中肿瘤坏死因子-1参与神经元损伤，而肿瘤坏死因子-2具有神经保护作用。目前尚不清楚肿瘤坏死因子-α及其受体是否对成人大脑中的神经发生起到任何作用。在这里，我们使用了失去肿瘤坏死因子-R1和肿瘤坏死因子-R2功能的小鼠模型，以确定通过这些受体的信号是否可以在基础条件下以及癫痫持续状态(SE)后影响活体海马神经发生，而癫痫持续状态(SE)与炎症和升高的TNF-α水平相关。值得注意的是，在完整的大脑中，新生的成熟海马神经元的数量在肿瘤坏死因子-R1(-/-)和肿瘤坏死因子-R1/R2(-/-)小鼠中增加，而在肿瘤坏死因子-R2(-/-)小鼠中没有检测到明显的变化。同样在SE后，肿瘤坏死因子-R1(-/-)和肿瘤坏死因子-R1/R2(-/-)小鼠产生了更多的新神经元。相反，肿瘤坏死因子-R2(-/-)小鼠表现出SE诱导的神经发生减少。在基础状态和SE后，肿瘤坏死因子-R1(-/-)和肿瘤坏死因子-R1/R2(-/-)小鼠齿状回颗粒下区细胞增殖均增强。肿瘤坏死因子-R2(-/-)小鼠的细胞增殖无变化或略有下降。分离或培养细胞的逆转录-聚合酶链式反应和免疫细胞化学检测海马祖细胞表达肿瘤坏死因子-1和肿瘤坏死因子-2受体。我们的数据揭示了肿瘤坏死因子-R1和肿瘤坏死因子-R2信号在成年海马神经发生中的不同作用，并首次发现肿瘤坏死因子-R1在正常脑和病理性脑中都是神经前体细胞增殖的负调控因子。
Tumor necrosis factor-alpha( TNF-alpha) is a proinflammatory cytokine, acting through the TNF-R1 and TNF-R2 receptors. The two receptors have been proposed to mediate distinct TNF-alpha effects in the CNS, TNF-R1 contributing to neuronal damage and TNF-R2 being neuroprotective. Whether TNF-alpha and its receptors play any role for neurogenesis in the adult brain is unclear. Here we used mouse models with loss of TNF-R1 and TNF-R2 function to establish whether signaling through these receptors could influence hippocampal neurogenesis in vivo under basal conditions, as well as after status epilepticus ( SE), which is associated with inflammation and elevated TNF-alpha levels. Notably, in the intact brain, the number of new, mature hippocampal neurons was elevated in TNF-R1(-/-) and TNF-R1/R2(-/-) mice, whereas no significant changes were detected in TNF-R2(-/-) mice. Also after SE, the TNF-R1(-/-) and TNF-R1/R2(-/-) mice produced more new neurons. In contrast, the TNF-R2(-/-) mice showed reduced SE-induced neurogenesis. Cell proliferation in the dentate subgranular zone was elevated in TNF-R1(-/-) and TNF-R1/R2(-/-) mice both under basal conditions and after SE. The TNF-R2(-/-) mice either showed no change or minor decrease of cell proliferation. TNF-R1 and TNF-R2 receptors were expressed by hippocampal progenitors, as assessed with reverse transcription-PCR on sorted or cultured cells and immunocytochemistry on cultures. Our data reveal differential actions of TNF-R1 and TNF-R2 signaling in adult hippocampal neurogenesis and identify for the first time TNF-R1 as a negative regulator of neural progenitor proliferation in both the intact and pathological brain.