Yang Zhenguo, Huang Chunnian, Wu Yongfu, Chen Bing, Zhang Wenqing, Zhang Jingjing
Department of Developmental Biology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China.
Affiliated Hospital of Guangdong Medical University, Zhanjiang, China.
Front Physiol. 2019 Jan 18;10:2. doi: 10.3389/fphys.2019.00002. eCollection 2019.
The blood-brain barrier (BBB) is essential for the exchange of nutrient and ions to maintain the homeostasis of central nervous system (CNS). BBB dysfunction is commonly associated with the disruption of endothelial tight junctions and excess permeability, which results in various CNS diseases. Therefore, maintaining the structural integrity and proper function of the BBB is essential for the homeostasis and physiological function of the CNS. Here, we showed that serum starvation disrupted the function of endothelial barrier as evidenced by decreased -endothelial electrical resistance, increased permeability, and redistribution of tight junction proteins such as Claudin-5 (Cldn5). Further analyses revealed that autophagy was activated and protected the integrity of endothelial barrier by scavenging ROS and inhibiting the redistribution of Cldn5 under starvation, as evidenced by accumulation of autophagic vacuoles and increased expression of LC3II/I, ATG5 and LAMP1. In addition, autophagosome was observed to package and eliminate the aggregated Cldn5 in cytosol as detected by immunoelectron microscopy (IEM) and stimulated emission depletion (STED) microscope. Moreover, Akt-mTOR-p70S6K pathway was found to be involved in the protective autophagy induced by starvation. Our data demonstrated that autophagy played an essential role in maintaining the integrity of endothelial barrier by regulating the localization of Cldn5 under starvation.
血脑屏障（BBB）对于营养物质和离子的交换至关重要，以维持中枢神经系统（CNS）的稳态。BBB功能障碍通常与内皮紧密连接的破坏和通透性增加有关，这会导致各种中枢神经系统疾病。因此，维持BBB的结构完整性和正常功能对于中枢神经系统的稳态和生理功能至关重要。在此，我们表明血清饥饿破坏了内皮屏障的功能，这表现为内皮电阻降低、通透性增加以及紧密连接蛋白如Claudin-5（Cldn5）的重新分布。进一步分析表明，自噬被激活，并通过清除活性氧和抑制饥饿状态下Cldn5的重新分布来保护内皮屏障的完整性，这表现为自噬空泡的积累以及LC3II/I、ATG5和LAMP1表达的增加。此外，通过免疫电子显微镜（IEM）和受激发射损耗（STED）显微镜检测发现，自噬体可包裹并清除细胞质中聚集的Cldn5。此外，发现Akt-mTOR-p70S6K通路参与了饥饿诱导的保护性自噬。我们的数据表明，自噬在饥饿状态下通过调节Cldn5的定位在维持内皮屏障完整性方面发挥了重要作用。
