Department of Neurology, Gongli Hospital, The Second Military Medical University, 219 Miaopu Road, Pudong New Area, Shanghai, 200135, People's Republic of China.
The Graduate School, Ningxia Medical University, Yinchuan, Ningxia, 750004, People's Republic of China.
J Neuroinflammation. 2020 Apr 7;17(1):107. doi: 10.1186/s12974-020-01780-x.
Although inflammatory cell adhesion molecules (CAMs) and anti-inflammation factor Kruppel-like transcription factor (KLF) 4 have all been reported to be induced after cerebral ischemic stroke (CIS), the close temporal and spatial relationship between expressions of CAMs and KLF4 following CIS and whether and how CAMs and KLF-4 contribute to the development of CIS-induced vascular injury are still unclear.
Here, we first examined the correlation between serum levels of CAMs/KLF4 and infarct volume in acute CIS patients. Then, we determined the relationship between CAMs and KLF4 in mice after focal cerebral ischemia. Finally, we investigated the mechanism of KLF4 in protecting against oxygen-glucose deprivation-induced brain endothelial cell injury.
Our results demonstrated that patients with moderate to severe CIS had higher serum levels of three CAMs including E-selectin, inter-cellular adhesion molecule 1 (ICAM-1), and vascular cell adhesion molecule 1 (VCAM-1) but lower levels of KLF4 at 48 h after an acute event as compared to patients with minor CIS. The expression levels of three CAMs as well as KLF4 all correlated well with the infarct volume in all the CIS subjects at that time. Although the expressions of three CAMs and KLF4 were all induced in the ischemic hemisphere following focal cerebral ischemia, the peak timing and distribution patterns of their expression were different: the induction of KLF4 lagged behind that of the CAMs in the ischemic penumbra; furthermore, the dual immunofluorescent studies displayed that high expression of KLF4 was always associated with relatively less cerebral vascular endothelial inflammation response in the ischemic hemisphere and vice versa. Mechanistic analyses revealed that KLF4 alleviated CIS-induced cerebral vascular injury by regulating endothelial expressions of CAMs, nuclear factor-kB, and tight junction proteins.
These data indicate that KLF4 confers vascular protection against cerebral ischemic injury, suggesting that circulating CAMs and KLF4 might be used as potential biomarkers for predicting the prognosis of acute ischemic stroke and also providing a new proof of concept and potential targets for future prevention and treatment of CIS.
尽管炎症细胞黏附分子（CAMs）和抗炎因子 Kruppel 样转录因子（KLF）4 在脑缺血性中风（CIS）后均被报道有诱导产生，但 CIS 后 CAMs 和 KLF4 的表达之间的紧密时空关系，以及 CAMs 和 KLF-4 是否以及如何有助于 CIS 诱导的血管损伤的发展仍不清楚。
在这里，我们首先检查了急性 CIS 患者中血清 CAMs/KLF4 水平与梗死体积之间的相关性。然后，我们确定了局灶性脑缺血后小鼠中 CAMs 和 KLF4 之间的关系。最后，我们研究了 KLF4 保护氧葡萄糖剥夺诱导的脑内皮细胞损伤的机制。
我们的结果表明，与轻度 CIS 患者相比，中度至重度 CIS 患者在急性事件后 48 小时血清中三种 CAMs（包括 E-选择素、细胞间黏附分子 1（ICAM-1）和血管细胞黏附分子 1（VCAM-1））水平较高，但 KLF4 水平较低。在所有 CIS 患者中，三种 CAMs 和 KLF4 的表达水平均与当时的梗死体积密切相关。尽管在局灶性脑缺血后缺血半球均诱导了三种 CAMs 和 KLF4 的表达，但它们的表达峰时间和分布模式不同：KLF4 的诱导滞后于缺血半影区的 CAMs；此外，双重免疫荧光研究显示，KLF4 的高表达总是与缺血半球中相对较少的脑血管内皮炎症反应相关，反之亦然。机制分析表明，KLF4 通过调节内皮细胞 CAMs、核因子-κB 和紧密连接蛋白的表达来减轻 CIS 引起的脑血管损伤。
这些数据表明，KLF4 赋予血管对脑缺血损伤的保护作用，提示循环 CAMs 和 KLF4 可能作为预测急性缺血性中风预后的潜在生物标志物，并为 CIS 的未来预防和治疗提供新的概念验证和潜在靶点。
