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

• Published in: Brain, behavior, and immunity Vol. 115; pp. 143 - 156
• Main Authors: Sun, Zhao-Wei, Wang, Xue, Zhao, Yun, Sun, Zhao-Xin, Wu, Yu-Han, Hu, Hui, Zhang, Ling, Wang, Shi-Da, Li, Feng, Wei, Ai-Jun, Feng, Hong, Xie, Fang, Qian, Ling-Jia
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier Inc 01.01.2024
• Subjects: Blood–brain barrier; Chronic stress; Depression; EZH2-Claudin-5 axis; H3K27me3 modification; TNF-α; Depression; Chronic stress; EZH2-Claudin-5 axis; TNF-α; H3K27me3 modification; Blood–brain barrier
• ISSN: 0889-1591; 1090-2139
• DOI: 10.1016/j.bbi.2023.10.010

•CUMS mice exhibits hippocampal BBB dysfunction accompanied with loss of Cldn5.•Enhanced recruitment of EZH2-dependent H3K27me3 modification at the Cldn5 promoter triggers its transcriptional repression and the subsequent depression in stressed individuals.•Chronic stress-induced BBB hyperpermeability is sufficient to allow TNF-α to infiltrate into the hippocampus contributing to depression-like behaviors.•Antidepressant treatment inhibits H3K37me3 deposition at the Cldn5 promoter to restore its expression and BBB function. 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 encoded protein and BBB damage. Considered together, these findings reveal the importance of the hippocampal EZH2-Claudin-5 axis in regulating neurovascular function and MDD development, providing potential therapeutic targets for this psychiatric illness.