Department of Neurosurgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University, School of Medicine, Shanghai, China.
Department of Ultrasound, Shanghai General Hospital, Shanghai Jiao Tong University, School of Medicine, Shanghai, China.
Front Immunol. 2023 Jun 14;14:1178638. doi: 10.3389/fimmu.2023.1178638. eCollection 2023.
The current approaches that are used to treat ischemic stroke suffer from poor targeting, lack of effectiveness, and potential off-target effects, necessitating the development of new therapeutic strategies to enhance neuronal cell survival and regeneration. This study aimed to investigate the role of microglial Netrin-1 in ischemic stroke, a topic that has not been fully understood.
Netrin-1 levels and its primary receptor expressions were investigated in cerebral microglia from acute ischemic stroke patients and age-matched control subjects. A public database (GEO148350), which supplied RNAseq results for rat cerebral microglia in a middle cerebral artery occlusion (MCAO) model, was analyzed to assess the expression of Netrin-1, its major receptors, and genes related to macrophage function. A microglia-specific gene targeting approach and a delivery system allowing for crossing the blood-brain barrier were applied in a mouse model for ischemic stroke to investigate the role of microglial Netrin-1. Netrin-1 receptor signaling in microglia was observed and the effects on microglial phenotype, apoptosis, and migration were analyzed.
Across human patients, rat and mouse models, activation of Netrin-1 receptor signaling was mainly conducted its receptor UNC5a in microglia, which resulted in a shift in microglial phenotype towards an anti-inflammatory or M2-like state, leading to a reduction in apoptosis and migration of microglia. Netrin-1-induced phenotypic change in microglia exerted protective effects on neuronal cells during ischemic stroke.
Our study highlights the potential of targeting Netrin-1 and its receptors as a promising therapeutic strategy for promoting post-ischemic survival and functional recovery.
目前用于治疗缺血性中风的方法存在靶向性差、效果不佳和潜在的脱靶效应等问题，因此需要开发新的治疗策略来增强神经元细胞的存活和再生。本研究旨在探讨微胶质细胞 Netrin-1 在缺血性中风中的作用，这一课题尚未得到充分理解。
检测了急性缺血性中风患者和年龄匹配的对照组脑内小胶质细胞中 Netrin-1 的水平及其主要受体表达。分析了一个公共数据库（GEO148350），该数据库提供了大脑中动脉闭塞（MCAO）模型中大鼠小胶质细胞的 RNAseq 结果，以评估 Netrin-1、其主要受体以及与巨噬细胞功能相关的基因的表达。在缺血性中风的小鼠模型中应用了一种小胶质细胞特异性基因靶向方法和一种可穿透血脑屏障的递送系统，以研究微胶质细胞 Netrin-1 的作用。观察了 Netrin-1 受体信号在小胶质细胞中的作用，并分析了其对小胶质细胞表型、凋亡和迁移的影响。
在人类患者、大鼠和小鼠模型中，Netrin-1 受体信号的激活主要通过其受体 UNC5a 在小胶质细胞中进行，导致小胶质细胞表型向抗炎或 M2 样状态转变，从而减少小胶质细胞的凋亡和迁移。Netrin-1 诱导小胶质细胞表型变化在缺血性中风中对神经元细胞发挥了保护作用。
本研究强调了靶向 Netrin-1 及其受体作为一种有前途的治疗策略的潜力，以促进缺血后存活和功能恢复。
