Qu Xinyi, Yang Ruicheng, Tan Chen, Chen Huanchun, Wang Xiangru
National Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, 430070, China.
Key Laboratory of Preventive Veterinary Medicine in Hubei Province, The Cooperative Innovation Center for Sustainable Pig Production, Wuhan, 430070, China.
Mol Neurobiol. 2025 Jan;62(1):661-673. doi: 10.1007/s12035-024-04303-4. Epub 2024 Jun 19.
The blood-brain barrier (BBB) is a complex structure that separates the central nervous system (CNS) from the peripheral blood circulation. Effective communication between different cell types within the BBB is crucial for its proper functioning and maintenance of homeostasis. In this study, we demonstrate that meningitic Escherichia coli (E. coli)-induced WNT5B plays a role in facilitating intercellular communication between astrocytes and brain microvascular endothelial cells (BMECs). We discovered that astrocytes-derived WNT5B activates the non-canonical WNT signaling pathway JNK/c-JUN in BMECs through its receptor ROR1, leading to inhibition of ZO-1 expression and impairment of the tight junction integrity in BMECs. Notably, our findings reveal that c-JUN, a transcription factor, directly regulates ZO-1 expression. By employing a dual luciferase reporting system and chromatin immunoprecipitation techniques, we identified specific binding sites of c-JUN on the ZO-1 promoter region. Overall, our study highlights the involvement of WNT5B in mediating intercellular communication between astrocytes and BMECs, provides insights into the role of WNT5B in meningitic E. coli-induced disruption of BBB integrity, and suggests potential therapeutic targeting of WNT5B as a strategy to address BBB dysfunction.
血脑屏障（BBB）是一种复杂的结构，它将中枢神经系统（CNS）与外周血液循环分隔开来。血脑屏障内不同细胞类型之间的有效通讯对于其正常功能和内环境稳态的维持至关重要。在本研究中，我们证明脑膜炎性大肠杆菌（E. coli）诱导的WNT5B在促进星形胶质细胞与脑微血管内皮细胞（BMECs）之间的细胞间通讯中发挥作用。我们发现星形胶质细胞衍生的WNT5B通过其受体ROR1激活BMECs中的非经典WNT信号通路JNK/c-JUN，导致ZO-1表达受到抑制以及BMECs中紧密连接完整性受损。值得注意的是，我们的研究结果表明转录因子c-JUN直接调节ZO-1的表达。通过使用双荧光素酶报告系统和染色质免疫沉淀技术，我们确定了c-JUN在ZO-1启动子区域的特异性结合位点。总体而言，我们的研究突出了WNT5B在介导星形胶质细胞与BMECs之间的细胞间通讯中的作用，深入了解了WNT5B在脑膜炎性大肠杆菌诱导的血脑屏障完整性破坏中的作用，并提出将WNT5B作为治疗靶点以解决血脑屏障功能障碍的潜在策略。
