KLF4 在调节缺血性中风后 A1/A2 反应性星形胶质细胞激活中的关键作用。

The critical role of KLF4 in regulating the activation of A1/A2 reactive astrocytes following ischemic stroke.

机构信息

Department of Neurology and Institute of Neurology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, People's Republic of China.

The Graduate School, Ningxia Medical University, Yinchuan, Ningxia, 750004, People's Republic of China.

出版信息

J Neuroinflammation. 2023 Feb 23;20(1):44. doi: 10.1186/s12974-023-02742-9.

BACKGROUND

We have previously demonstrated that the expression of kruppel-like transcription factor-4 (KLF-4) is upregulated in astrocytes following acute ischemic stroke (AIS) and found that KLF4 confers vascular protection against cerebral ischemic injury. However, the functional role of KLF4 in astrocyte after AIS is far from clear.

METHODS

The intrinsic relationship between KLF4 and A1/A2 reactive astrocytes and the impact of astrocytic KLF4 on the activation of A1/A2 subtype astrocytes were evaluated in middle cerebral artery occlusion (MCAO) mice and oxygen-glucose deprivation and restoration (OGD/R) astrocytes.

RESULTS

Our results demonstrated that astrocytic KLF4 expression and complement C3-positive A1 and S100 calcium binding protein A10 (S100A10)-positive A2 astrocytes were induced in the ischemic penumbra following focal cerebral ischemia, and the time course of upregulation of astrocytic KLF4 correlated closely with the activation of A2 astrocytes. The dual immunofluorescent studies displayed that in the ischemic hemisphere, where the high levels of KLF4 were expressed, there were relatively low levels of C3 expressed in the reactive astrocytes and vice versa, but KLF4 was always co-stained well with S100A10. Mechanistic analyses revealed that astrocytic KLF4 inhibited the activation of A1 astrocyte but promoted A2 astrocyte polarization after OGD/R by modulating expressions of nuclear factor-kB.

CONCLUSIONS

Astrocyte-derived KLF4 has a critical role in regulating the activation of A1/A2 reactive astrocytes following AIS.

背景

我们之前已经证明，在急性缺血性脑卒中（AIS）后星形胶质细胞中 kruppel 样转录因子-4（KLF-4）的表达上调，并发现 KLF4 对脑缺血损伤具有血管保护作用。然而，KLF4 在 AIS 后星形胶质细胞中的功能作用尚不清楚。

方法

在大脑中动脉闭塞（MCAO）小鼠和氧葡萄糖剥夺和恢复（OGD/R）星形胶质细胞中，评估了 KLF4 与 A1/A2 反应性星形胶质细胞之间的内在关系，以及星形胶质细胞 KLF4 对 A1/A2 亚型星形胶质细胞激活的影响。

结果

我们的研究结果表明，在局灶性脑缺血后缺血半影区诱导了星形胶质细胞 KLF4 表达和补体 C3 阳性的 A1 和 S100 钙结合蛋白 A10（S100A10）阳性的 A2 星形胶质细胞，星形胶质细胞 KLF4 的上调时间过程与 A2 星形胶质细胞的激活密切相关。双重免疫荧光研究显示，在高表达 KLF4 的缺血半球中，反应性星形胶质细胞中 C3 的表达水平相对较低，反之亦然，但 KLF4 总是与 S100A10 很好地共染色。机制分析表明，星形胶质细胞 KLF4 通过调节核因子-kB 的表达，抑制 OGD/R 后 A1 星形胶质细胞的激活，但促进 A2 星形胶质细胞的极化。