Microglia activation contributes to quinolinic acid-induced neuronal excitotoxicity through TNF-α
Microglia activation contributes to quinolinic acid-induced neuronal excitotoxicity through TNF-α
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小胶质细胞激活通过 TNF-α 促进喹啉酸诱导的神经元兴奋毒性
DOI：
10.1007/s10495-017-1363-5
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发表时间：
2017-05-01
期刊：
影响因子：
7.2
通讯作者：
Qin, Zheng-Hong
中科院分区：
文献类型：
--
作者：
Feng, Wei;Wang, Yan;Qin, Zheng-Hong
据报道，NF-kappa B 的激活与兴奋性毒性有关；然而，目前尚不完全了解 NF-kappa B 如何导致兴奋性毒性。本研究的目的是调查 NF-kappa B 是否通过激活小胶质细胞导致喹啉酸 (QA) 介导的兴奋性毒性。在培养的原代皮质神经元和小胶质细胞 BV-2 细胞中，研究了 QA 对细胞存活、NF-κ B 表达和细胞因子产生的影响。检查了 BV-2 条件培养基 (BCM) 对原代皮质神经元的影响。评估了吡咯烷二硫代氨基甲酸酯 (PDTC)（一种 NF-κ B 抑制剂）和米诺环素（MC）（一种小胶质细胞激活抑制剂）对 QA 诱导的兴奋性毒性的影响。研究了 QA 诱导的 NF-κ B 激活和 TNF-α 分泌，以及 TNF-α 在兴奋性毒性中的作用。浓度低于1 mM的QA对培养的原代神经元或BV-2细胞没有明显的毒性作用。然而，向原代神经元添加 QA 引发的 BCM 确实会加剧 QA 诱导的兴奋性毒性。 BCM 引起的 QA 诱导的兴奋性毒性的加剧可通过抑制 NF-κ B 和小胶质细胞的激活得到部分缓解。 QA 诱导 BV-2 细胞中 NF-κ B 的激活和 TNF-α 的上调。添加重组 TNF-α 模拟 QA 诱导的神经元兴奋性毒性作用，并用特异性抗体中和 TNF-α，部分消除了 BCM 引起的 QA 诱导的兴奋性毒性的加剧。这些研究表明，QA 激活小胶质细胞并通过小胶质细胞中的 NF-κ B 通路上调 TNF-α。小胶质细胞介导的炎症途径至少部分地导致了 QA 诱导的兴奋性毒性。
It has been reported that activation of NF-kappa B is involved in excitotoxicity; however, it is not fully understood how NF-kappa B contributes to excitotoxicity. The aim of this study is to investigate if NF-kappa B contributes to quinolinic acid (QA)-mediated excitotoxicity through activation of microglia. In the cultured primary cortical neurons and microglia BV-2 cells, the effects of QA on cell survival, NF-kappa B expression and cytokines production were investigated. The effects of BV-2-conditioned medium (BCM) on primary cortical neurons were examined. The effects of pyrrolidine dithiocarbamate (PDTC), an inhibitor of NF-kappa B, and minocycline (MC), an inhibitor of microglia activation, on QA-induced excitotoxicity were assessed. QA-induced NF-kappa B activation and TNF-alpha secretion, and the roles of TNF-alpha in excitotoxicity were studied. QA at the concentration below 1 mM had no apparent toxic effects on cultured primary neurons or BV-2 cells. However, addition of QA-primed BCM to primary neurons did aggravate QA-induced excitotoxicity. The exacerbation of QA-induced excitotoxicity by BCM was partially ameliorated by inhibiting NF-kappa B and microglia activation. QA induced activation of NF-kappa B and upregulation of TNF-alpha in BV-2 cells. Addition of recombinant TNF-alpha mimicked QA-induced excitotoxic effects on neurons, and neutralizing TNF-alpha with specific antibodies partially abolished exacerbation of QA-induced excitotoxicity by BCM. These studies suggested that QA activated microglia and upregulated TNF-alpha through NF-kappa B pathway in microglia. The microglia-mediated inflammatory pathway contributed, at least in part, to QA-induced excitotoxicity.