Abstract：
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.
摘要：
血脑屏障（BBB）是将中枢神经系统（CNS）与外周血循环分开的复杂结构。BBB内不同细胞类型之间的有效通讯对于其正常运作和维持体内平衡至关重要。在这项研究中,我们证明了脑膜炎大肠杆菌(E.大肠杆菌）诱导的WNT5B在促进星形胶质细胞和脑微血管内皮细胞（BMEC）之间的细胞间通讯中起作用。我们发现星形胶质细胞来源的WNT5B通过其受体ROR1激活BMEC中非经典WNT信号通路JNK/c-JUN，导致BMEC中ZO-1表达抑制和紧密连接完整性受损。值得注意的是,我们的发现表明c-JUN,转录因子，直接调控ZO-1的表达。通过采用双荧光素酶报告系统和染色质免疫沉淀技术，我们在ZO-1启动子区鉴定了c-JUN的特异性结合位点。总的来说,我们的研究强调了WNT5B参与介导星形胶质细胞和BMEC之间的细胞间通讯，提供了对WNT5B在脑膜炎大肠杆菌诱导的BBB完整性破坏中的作用的见解，并提示WNT5B的潜在治疗靶向作为解决BBB功能障碍的策略。
