Key Laboratory of Molecular and Developmental Biology, Institute of Genetics and Developmental Biology, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Beijing, China.
Institute of Neuroscience, National Yang Ming Chiao Tung University, Taipei, Taiwan.
Elife. 2024 Oct 31;12:RP87258. doi: 10.7554/eLife.87258.
Traumatic brain injury (TBI) caused by external mechanical forces is a major health burden worldwide, but the underlying mechanism in glia remains largely unclear. We report herein that adults exhibit a defective blood-brain barrier, elevated innate immune responses, and astrocyte swelling upon consecutive strikes with a high-impact trauma device. RNA sequencing (RNA-seq) analysis of these astrocytes revealed upregulated expression of genes encoding PDGF and VEGF receptor-related (Pvr, a receptor tyrosine kinase), adaptor protein complex 1 (AP-1 a transcription factor complex of the c-Jun N-terminal kinase pathway) composed of Jun-related antigen (Jra) and kayak (kay), and matrix metalloproteinase 1 (Mmp1) following TBI. Interestingly, Pvr is both required and sufficient for AP-1 and Mmp1 upregulation, while knockdown of AP-1 expression in the background of Pvr overexpression in astrocytes rescued Mmp1 upregulation upon TBI, indicating that Pvr acts as the upstream receptor for the downstream AP-1-Mmp1 transduction. Moreover, dynamin-associated endocytosis was found to be an important regulatory step in downregulating Pvr signaling. Our results identify a new Pvr-AP-1-Mmp1 signaling pathway in astrocytes in response to TBI, providing potential targets for developing new therapeutic strategies for TBI.
创伤性脑损伤（TBI）是由外部机械力引起的，是全球范围内的一个主要健康负担，但胶质细胞中的潜在机制在很大程度上仍不清楚。我们在此报告，成年人在连续受到高冲击力创伤装置打击后，会出现血脑屏障缺陷、固有免疫反应升高和星形胶质细胞肿胀。对这些星形胶质细胞进行的 RNA 测序（RNA-seq）分析显示，编码血小板衍生生长因子和血管内皮生长因子受体相关（Pvr，一种受体酪氨酸激酶）、衔接蛋白复合物 1（AP-1，c-Jun N 末端激酶途径的转录因子复合物，由 Jun 相关抗原（Jra）和 kayak（kay）组成）和基质金属蛋白酶 1（Mmp1）的基因表达上调。有趣的是，Pvr 是 AP-1 和 Mmp1 上调所必需和充分的，而在星形胶质细胞中过表达 Pvr 的背景下敲低 AP-1 表达可挽救 TBI 后 Mmp1 的上调，表明 Pvr 作为下游 AP-1-Mmp1 转导的上游受体。此外，还发现与 dynamin 相关的内吞作用是下调 Pvr 信号的重要调节步骤。我们的研究结果确定了星形胶质细胞中对 TBI 反应的新的 Pvr-AP-1-Mmp1 信号通路，为开发 TBI 的新治疗策略提供了潜在的靶点。
