Glutaminase 1 Regulates Neuroinflammation After Cerebral Ischemia Through Enhancing Microglial Activation and Pro-Inflammatory Exosome Release

被引：71

作者：

Gao, Ge ^{[1
]}

Li, Congcong ^{[1
]}

Zhu, Jie ^{[1
]}

Wang, Yi ^{[1
]}

Huang, Yunlong ^{[1
,2
,3
]}

Zhao, Shu ^{[1
]}

Sheng, Shiyang ^{[1
]}

Song, Yu ^{[1
]}

Ji, Chenhui ^{[1
]}

Li, Chunhong ^{[1
]}

Yang, Xiaoyu ^{[1
]}

Ye, Ling ^{[1
]}

Qi, Xinrui ^{[1
]}

Zhang, Yanyan ^{[1
]}

Xia, Xiaohuan ^{[1
]}

Zheng, Jialin C. ^{[1
,2
,3
,4
]}

机构：

[1] Tongji Univ, Sch Med, Shanghai Peoples Hosp 10, Ctr Translat Neurodegenerat & Regenerat Therapy, Shanghai, Peoples R China

[2] Univ Nebraska Med Ctr, Dept Pharmacol, Omaha, NE 68198 USA

[3] Univ Nebraska Med Ctr, Dept Expt Neurosci, Omaha, NE 68198 USA

[4] Tongji Univ, Collaborat Innovat Ctr Brain Sci, Shanghai, Peoples R China

来源：

FRONTIERS IN IMMUNOLOGY | 2020年 / 11卷

基金：

中国国家自然科学基金; 中国博士后科学基金; 美国国家卫生研究院;

关键词：

focal cerebral ischemia; glutaminase; 1; microglial activation; brain inflammation; glutaminase inhibitor; exosome; HIV-1-INFECTED MACROPHAGES; MITOCHONDRIAL GLUTAMINASE; EXTRACELLULAR VESICLES; GLUTAMATE; CYTOKINES; KINETICS; DEFICITS; CULTURES; STROKE; DAMAGE;

D O I：

10.3389/fimmu.2020.00161

中图分类号：

R392 [医学免疫学]; Q939.91 [免疫学];

学科分类号：

100102 ;

摘要：

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 in vitro. 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.

引用

页数：12

共 39 条

[11] Glutaminase Dysregulation in HIV-1-Infected Human Microglia Mediates Neurotoxicity: Relevant to HIV-1-Associated Neurocognitive Disorders [J].