Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China; Cardiovascular Research Institute of Wuhan University, Wuhan, China.
J Neurochem. 2014 Jun;129(6):988-1001. doi: 10.1111/jnc.12682. Epub 2014 Mar 13.
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. In the present study, we found that the transcriptional factor IRF8 plays a protective role in the cerebral ischaemic-reperfusion injury by attenuating neuronal apoptosis, oxidative stress and inflammation. Besides the known function of IRF8 in regulating the inflammatory gene expression, we first demonstrated that IRF8 can directly modulate apoptosis and oxidative stress by controlling the relative genes expression.
干扰素调节因子 8（IRF8）是 IRF 家族中的一种转录调节因子，与先天免疫、免疫细胞分化和肿瘤细胞凋亡有关。在本研究中，我们发现 IRF8 在大脑中持续表达，在脑缺血后呈时间依赖性抑制。我们使用短暂性脑缺血模型，对 IRF8 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进行研究。IRF8 敲除小鼠缺血大脑中的细胞凋亡、炎症和氧化损伤加重，最终导致更差的中风结局，而神经元特异性 IRF8 转基因小鼠则表现出明显的细胞凋亡抑制和中风结局改善。为了在体外模拟缺血/再灌注条件，我们培养原代皮质神经元并进行 60 分钟的短暂氧葡萄糖剥夺。与体内研究相似，Ad-shIRF8 下调 IRF8 导致细胞凋亡增加，而 Ad-IRF8 过表达则显著降低神经元凋亡。这些数据表明，IRF8 通过调节神经元凋亡、炎症反应和氧化应激，在缺血性中风中具有很强的保护作用。在本研究中，我们发现转录因子 IRF8 通过减轻神经元凋亡、氧化应激和炎症在脑缺血再灌注损伤中发挥保护作用。除了已知的 IRF8 调节炎症基因表达的功能外，我们首次证明 IRF8 可以通过控制相关基因的表达来直接调节细胞凋亡和氧化应激。
