Department of Neurology, The Fourth Affiliated Hospital of China Medical University, Shenyang, China.
J Cell Physiol. 2019 May;234(5):7341-7355. doi: 10.1002/jcp.27493. Epub 2018 Oct 26.
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-κB (PI3K/Akt/NF-κB)-signaling pathway. In this study, we aimed to explore the mechanism of CXCL8 in ischemic stroke in relation to the PI3K/Akt/NF-κB-signaling pathway.
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-1β, tumor necrosis factor-α (TNF-α), Akt, PI3K, and NF-κB were determined.
Comprehensive gene expression profiling analysis identified that CXCL8 might affect the development of ischemic stroke through regulating the PI3K/Akt/NF-κB-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.
Taken together, these findings highlight that functional suppression of CXCL8 promotes neuroglial activation and inhibits neuroinflammation by regulating the PI3K/Akt/NF-κB-signaling pathway in mice with ischemic stroke, which might provide new insight for ischemic stroke treatment.
缺血性脑卒中是一种神经退行性疾病，可导致长时间的组织损伤。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-κB（PI3K/Akt/NF-κB）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 在缺血性脑卒中相关的 PI3K/Akt/NF-κB 信号通路中的作用机制。
使用基于微阵列的外周血单个核细胞基因表达谱分析来鉴定与缺血性脑卒中相关的差异表达基因，并探讨 CXCL8 在缺血性脑卒中中的作用。然后，成功建立了缺血性脑卒中模型，并检测了转染效率。之后，测量了缺血性脑卒中的偏转角、神经系统恢复、梗死面积、缺血诱导的细胞凋亡和神经炎症反应。最后，测定了炎症因子的含量以及 CXCL8、半胱氨酸天冬氨酸蛋白酶-3（caspase-3）、半胱氨酸天冬氨酸蛋白酶-9（caspase-9）、Bad、白细胞介素-6（IL-6）、白细胞介素-1β（IL-1β）、肿瘤坏死因子-α（TNF-α）、Akt、PI3K 和 NF-κB 的表达。
综合基因表达谱分析表明，CXCL8 可能通过调节 PI3K/Akt/NF-κB 信号通路影响缺血性脑卒中的发展。沉默 CXCL8 可显著降低偏转角和梗死面积，改善神经功能，并抑制神经胶质细胞丢失和凋亡指数。此外，沉默 CXCL8 可降低胶质纤维酸性蛋白（GFAP）和离子钙结合接头蛋白 1（IBA-1）的表达，提示 CXCL8 影响神经胶质细胞的激活。重要的是，我们还发现，沉默 CXCL8 可激活缺血性脑卒中小鼠的神经胶质细胞并抑制炎症细胞因子的产生。
综上所述，这些发现强调了通过调节 PI3K/Akt/NF-κB 信号通路，功能性抑制 CXCL8 可促进缺血性脑卒中小鼠的神经胶质细胞激活和抑制神经炎症，这可能为缺血性脑卒中的治疗提供新的思路。
