Interferon regulatory factor 8 protects against cerebral ischaemic‐reperfusion injury
Interferon regulatory factor 8 protects against cerebral ischaemic‐reperfusion injury
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DOI：
10.1111/jnc.12682
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发表时间：
2014-06
影响因子：
4.7
通讯作者：
Mei Xiang;Lang Wang;Sen Guo;Yanyun Lu;H. Lei;D. Jiang;Yan Zhang;Yi Liu;Yan Zhou;Xiao-dong Z
中科院分区：
文献类型：
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作者：
Mei Xiang;Lang Wang;Sen Guo;Yanyun Lu;H. Lei;D. Jiang;Yan Zhang;Yi Liu;Yan Zhou;Xiao-dong Z
干扰素调节因子8(IRF8)是IRF家族中的一种转录调节因子，参与天然免疫、免疫细胞分化和肿瘤细胞的凋亡。在目前的研究中，我们发现IRF8在脑内呈结构性表达，并在脑缺血后以时间依赖的方式被抑制。用IRF8基因敲除(IRF8-KO)小鼠、野生型(WT)小鼠、神经元特异性IRF8转基因(TG)小鼠和非转基因小鼠建立短暂性脑缺血模型。IRF8基因敲除小鼠表现出缺血脑中严重的细胞凋亡、炎症和氧化损伤，最终导致较差的卒中结果，而神经元特异性IRF8转基因小鼠显示出明显的细胞凋亡抑制和改善卒中结果。为了模拟体外缺血/再灌注条件，原代培养的大脑皮层神经元在短暂的缺氧和缺糖条件下60min。与体内研究类似，Ad-shIRF8敲除IRF8可导致神经细胞凋亡增加，而Ad-IRF8过表达IRF8可显著减少神经细胞凋亡。这些数据表明，IRF8通过调节神经细胞凋亡、炎症反应和氧化应激，对缺血性卒中具有很强的保护作用。
Interferon regulatory factor 8 (IRF8), a transcriptional regulator in the IRF family, has been implicated in innate immunity, immune cell differentiation and tumour cell apoptosis. In the present study, we found that IRF8 is constitutively expressed in the brain and suppressed after cerebral ischaemia in a time‐dependent manner. IRF8 knockout (IRF8‐KO) mice, wild type (WT) mice, neuron‐specific IRF8 transgenic (TG) mice and non‐transgenic mice were used in a transient cerebral ischaemic model. The IRF8 knockout mice exhibited aggravated apoptosis, inflammation and oxidative injury in the ischaemic brain, eventually leading to poorer stroke outcomes, whereas neuron‐specific IRF8 transgenic mice showed a marked inhibition of apoptosis and improved stroke outcomes. To model ischaemia/reperfusion conditions in vitro, primary cortical neurons were cultured and subjected to transient oxygen and glucose deprivation for 60 min. Similar to the in vivo study, IRF8 knockdown by Ad‐shIRF8 resulted in increased apoptosis, whereas IRF8 over‐expression by Ad‐IRF8 significantly decreased neuronal apoptosis. These data indicate that IRF8 is strongly protective in ischaemic stroke by regulating neuronal apoptosis, the inflammatory response and oxidative stress.