Center for Translational Neurodegeneration and Regenerative Therapy, Shanghai Tenth People's Hospital Affiliated to Tongji University School of Medicine, Shanghai, China.
Departments of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE, United States.
Front Immunol. 2020 Feb 7;11:161. doi: 10.3389/fimmu.2020.00161. eCollection 2020.
Cerebral ischemia induces a robust neuroinflammatory response that is largely mediated by the activation of CNS resident microglia. Activated microglia produce pro-inflammatory molecules to cause neuronal damage. Identifying regulators of microglial activation bears great potential in discovering promising candidates for neuroprotection post cerebral ischemia. Previous studies demonstrate abnormal elevation of glutaminase 1 (GLS1) in microglia in chronic CNS disorders including Alzheimer's disease and HIV-associated neurocognitive disorders. Ectopic expression of GLS1 induced microglia polarization into pro-inflammatory phenotype and exosome release . However, whether GLS1 is involved in neuroinflammation in acute brain injury remains unknown. Here, we observed activation of microglia, elevation of GLS1 expression, and accumulation of pro-inflammatory exosomes in rat brains 72 h post focal cerebral ischemia. Treatment with CB839, a glutaminase inhibitor, reversed ischemia-induced microglial activation, inflammatory response, and exosome release. Furthermore, we found that the application of exosome secretion inhibitor, GW4869, displayed similar anti-inflammatory effects to that of CB839, suggesting GLS1-mediated exosome release may play an important role in the formation of neuroinflammatory microenvironment. Therefore, GLS1 may serve as a key mediator and promising target of neuroinflammatory response in cerebral ischemia.
脑缺血诱导强烈的神经炎症反应，主要由中枢神经系统常驻小胶质细胞的激活介导。激活的小胶质细胞产生促炎分子导致神经元损伤。鉴定小胶质细胞激活的调节剂在发现脑缺血后有希望的神经保护候选物方面具有巨大潜力。先前的研究表明，在包括阿尔茨海默病和 HIV 相关神经认知障碍在内的慢性中枢神经系统疾病中小胶质细胞中谷氨酰胺酶 1 (GLS1)异常升高。GLS1 的异位表达诱导小胶质细胞极化为促炎表型并释放外泌体。然而，GLS1 是否参与急性脑损伤中的神经炎症仍不清楚。在这里，我们观察到在局灶性脑缺血后 72 小时大鼠脑中小胶质细胞的激活、GLS1 表达的升高和促炎外泌体的积累。用谷氨酰胺酶抑制剂 CB839 处理可逆转缺血诱导的小胶质细胞激活、炎症反应和外泌体释放。此外，我们发现外泌体分泌抑制剂 GW4869 的应用显示出与 CB839 相似的抗炎作用，表明 GLS1 介导的外泌体释放可能在神经炎症微环境的形成中起重要作用。因此，GLS1 可能作为脑缺血中神经炎症反应的关键介质和有希望的靶标。
