CXCL8 gene silencing promotes neuroglial cells activation while inhibiting neuroinflammation through the PI3K/Akt/NF-κB-signaling pathway in mice with ischemic stroke
CXCL8 gene silencing promotes neuroglial cells activation while inhibiting neuroinflammation through the PI3K/Akt/NF-κB-signaling pathway in mice with ischemic stroke
复制标题
CXCL8基因沉默通过PI3K/Akt/NF-κB信号通路促进缺血性脑卒中小鼠神经胶质细胞活化，同时抑制神经炎症 。
DOI：
10.1002/jcp.27493
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发表时间：
2019-05-01
影响因子：
5.6
通讯作者：
Che, Yu-Qin
中科院分区：
文献类型：
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作者：
Lv, Hui;Li, Jie;Che, Yu-Qin
目的缺血性中风是一种神经退行性疾病，可引起长时间的组织损伤。趋化因子（C-X-C基序）配体8 （CXCL8）通过磷酸肌醇-3激酶/蛋白激酶B/核因子κ B （PI3K/Akt/ nf - κ B）信号通路参与急性炎症和肿瘤进展。在本研究中，我们旨在探讨CXCL8在缺血性卒中中与PI3K/Akt/ nf - κ b信号通路的关系。方法采用外周血单核细胞微阵列基因表达谱检测缺血性脑卒中相关差异表达基因，探讨CXCL8在缺血性脑卒中中的作用。成功建立缺血小鼠模型，检测转染效率。测量脑缺血后的偏转指数、神经系统恢复情况、梗死面积、缺血诱导的细胞凋亡及神经炎症反应。最后，检测炎症因子的含量以及CXCL8、caspase-3、caspase-9、Bad、白细胞介素-6 （IL-6）、IL-1 β、肿瘤坏死因子- α (tnf - α)、Akt、PI3K、nf - κ B的表达。结果综合基因表达谱分析发现，CXCL8可能通过调控PI3K/Akt/ nf - κ b信号通路影响缺血性卒中的发生。CXCL8沉默显著降低偏转指数和梗死面积，改善神经功能，抑制神经胶质细胞损失和凋亡指数。此外，CXCL8抑制后，神经胶质纤维酸性蛋白（GFAP）和离子钙结合适配器分子1 （IBA-1）的表达降低，表明CXCL8影响神经胶质的活化。重要的是，我们还发现CXCL8沉默激活了缺血性中风小鼠的神经胶质细胞并抑制了炎症细胞因子的产生。综上所示，CXCL8的功能抑制可能通过调控PI3K/Akt/ nf - κ b信号通路促进缺血性脑卒中小鼠神经胶质细胞活化，抑制神经炎症，为缺血性脑卒中治疗提供新的思路。
Objective Ischemic stroke is known as a neurodegenerative disorder, which induces long-period tissue damage. Chemokine (C-X-C motif) ligand 8 (CXCL8) is involved in acute inflammation and tumor progression through the phosphoinositide-3-kinase/protein kinase B/nuclear factor-kappa B (PI3K/Akt/NF-kappa B)-signaling pathway. In this study, we aimed to explore the mechanism of CXCL8 in ischemic stroke in relation to the PI3K/Akt/NF-kappa B-signaling pathway. Methods Microarray-based gene expression profiling of peripheral blood mononuclear cells was used to identify ischemic stroke-related differentially expressed genes and explore role of CXCL8 in ischemic stroke. Next, the ischemic mice model was successfully established, with transfection efficiency detected. After that, deflection index, recovery of nervous system, infarct sizes, ischemia-induced apoptosis, and neuroinflammatory response in ischemic stroke were measured. At last, the content of inflammatory factors as well as the expression of CXCL8, caspase-3, caspase-9, Bad, interleukin-6 (IL-6), IL-1 beta, tumor necrosis factor-alpha (TNF-alpha), Akt, PI3K, and NF-kappa B were determined. Results Comprehensive gene expression profiling analysis identified that CXCL8 might affect the development of ischemic stroke through regulating the PI3K/Akt/NF-kappa B-signaling pathway. CXCL8 silencing significantly reduced deflection index and infarct size, improved neurological function, and suppressed neuroglial cell loss and apoptosis index. In addition, glial fibrillary acidic portein (GFAP) and ionized calcium-binding adapter molecule 1 (IBA-1) expressions were decreased following CXCL8 suppression, suggesting CXCL8 affected neuroglial activation. Importantly, we also found that CXCL8 silencing activated neuroglial cell and suppressed inflammatory cytokine production in ischemic stroke mice. Conclusion Taken together, these findings highlight that functional suppression of CXCL8 promotes neuroglial activation and inhibits neuroinflammation by regulating the PI3K/Akt/NF-kappa B-signaling pathway in mice with ischemic stroke, which might provide new insight for ischemic stroke treatment.