Blood-brain barrier dysfunction mediated by the EZH2-Claudin-5 axis drives stress-induced TNF-α infiltration and depression-like behaviors

作者：Zhaowei Sun, Xue Wang, Yun Zhao, Zhao-Xin Sun, Yuhan Wu, Hui Hu, Ling Zhang, Shi-Da Wang, Feng Li, Aijun Wei, Feng Hong, Fang Xie, Lingjia Qian · 发表于：Brain Behavior and Immunity · 年份：2023 · DOI：10.1016/j.bbi.2023.10.010 · 被引用次数：97 · 研究领域：Tryptophan and brain disorders、Neuroinflammation and Neurodegeneration Mechanisms、Gut microbiota and health

Growing evidence suggests that neurovascular dysfunction characterized by blood-brain barrier (BBB) breakdown underlies the development of psychiatric disorders, such as major depressive disorder (MDD). Tight junction (TJ) proteins are critical modulators of homeostasis and BBB integrity. TJ protein Claudin-5 is the most dominant BBB component and is downregulated in numerous depression models; however, the underlying mechanisms remain elusive. Here, we demonstrate a molecular basis of BBB breakdown that links stress and depression. We implemented an animal model of depression, chronic unpredictable mild stress (CUMS) in male C57BL/6 mice, and showed that hippocampal BBB breakdown was closely associated with stress vulnerability. Concomitantly, we found that dysregulated Cldn5 level coupled with repression of the histone methylation signature at its promoter contributed to stress-induced BBB dysfunction and depression. Moreover, histone methyltransferase enhancer of zeste homolog 2 (EZH2) knockdown improved Cldn5 expression and alleviated depression-like behaviors by suppressing the tri-methylation of lysine 27 on histone 3 (H3K27me3) in chronically stressed mice. Furthermore, the stress-induced excessive transfer of peripheral cytokine tumor necrosis factor-α (TNF-α) into the hippocampus was prevented by Claudin-5 overexpression and EZH2 knockdown. Interestingly, antidepressant treatment could inhibit H3K27me3 deposition at the Cldn5 promoter, reversing the loss of the encod...