KLF4 Knockdown Attenuates TBI-Induced Neuronal Damage through p53 and JAK-STAT3 Signaling
KLF4 Knockdown Attenuates TBI-Induced Neuronal Damage through p53 and JAK-STAT3 Signaling
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DOI：
10.1111/cns.12633
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发表时间：
2017-02-01
影响因子：
5.5
通讯作者：
Gao, Liang
中科院分区：
文献类型：
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作者：
Cui, Da-Ming;Zeng, Tao;Gao, Liang
创伤性脑损伤（TBI）是由复杂的原发性和继发性机制引起的，这些机制导致细胞死亡、炎症和神经功能障碍。了解驱动神经损伤的机制以及促进修复的机制可以指导TBI治疗药物的开发。Kruppel样因子4（KLF 4）通过抑制JAK-STAT 3信号通路负调控受损视网膜神经节细胞（RGC）轴突再生。然而，KLF 4在TBI中的作用尚未报道。活性氧（ROS）诱导的神经元死亡是TBI.MethodsIn这项研究中，我们使用过氧化氢处理的RGCs在体外和视神经挤压模型在体内模拟神经元损伤TBI的病理生理学标志。在这些模型中，研究KLF 4在RGC存活和轴突再生中的功能。此外，KLF 4敲低对神经元损伤的影响后，模拟中度TBIwered.ResultsThe结果表明，H2 O2诱导p53依赖性细胞凋亡的RGCs在体外通过上调KLF 4。此外，KLF 4在体内敲低显著增强CNTF诱导的视神经挤压后RGCs轴突再生，更重要的是，防止大鼠中度脑损伤后的神经元损伤。我们的Western印迹分析和免疫沉淀试验结果表明，这些影响KLF 4敲低介导的p53和JAK-STAT 3 pathways.ConclusionThese研究结果提供证据表明，KLF 4在TBI的病理生理学中起着重要作用。阻断KLF 4可能是治疗TBI的潜在治疗策略，无论是单独使用还是与靶向互补机制的药物联合使用。
AimsTraumatic brain injury (TBI) is induced by complex primary and secondary mechanisms that give rise to cell death, inflammation, and neurological dysfunction. Understanding the mechanisms that drive neurological damage as well as those that promote repair can guide the development of therapeutic drugs for TBI. Kruppel-like factor 4 (KLF4) has been reported to negatively regulate axon regeneration of injured retinal ganglion cells (RGCs) through inhibition of JAK-STAT3 signaling. However, the role of KLF4 in TBI remains unreported. Reactive oxygen species (ROS)-induced neuronal death is a pathophysiological hallmark of TBI.MethodsIn this study, we used H2O2-treated RGCs in vitro and the optic nerve crush model in vivo to simulate neuronal damage in TBI. The function of KLF4 in RGC survival and axon regeneration in these models was investigated. In addition, the effects of KLF4 knockdown on neuronal damage after a brain impact that mimics moderate TBI were studied.ResultsThe results show that H2O2 induces p53-dependent apoptosis of RGCs in vitro through upregulation of KLF4. Additionally, KLF4 knockdown in vivo significantly enhances CNTF-induced axon regeneration of RGCs after optic nerve crush, and more importantly, prevents neuronal damage after a moderate brain impact in rats. Our Western blot analysis and immunoprecipitation assay results indicate that these effects of KLF4 knockdown are mediated by the p53 and JAK-STAT3 pathways.ConclusionThese findings provide evidence that KLF4 plays an important role in the pathophysiology of TBI. Blocking KLF4 may be a potential therapeutic strategy for the treatment of TBI, either alone or in combination with agents that target complementary mechanisms.