TY - JOUR
T1 - Glutaminase 1 Regulates Neuroinflammation After Cerebral Ischemia Through Enhancing Microglial Activation and Pro-Inflammatory Exosome Release
AU - Gao, Ge
AU - Li, Congcong
AU - Zhu, Jie
AU - Wang, Yi
AU - Huang, Yunlong
AU - Zhao, Shu
AU - Sheng, Shiyang
AU - Song, Yu
AU - Ji, Chenhui
AU - Li, Chunhong
AU - Yang, Xiaoyu
AU - Ye, Ling
AU - Qi, Xinrui
AU - Zhang, Yanyan
AU - Xia, Xiaohuan
AU - Zheng, Jialin C.
N1 - Funding Information:
We kindly acknowledge Ms. Yuju Li and Lu Ding who provided valuable technical support about the manuscript. Funding. This work was supported in part by research grants from the State Key Program of the National Natural Science Foundation of China (No. 81830037 to JCZ), the National Basic Research Program of China (973 Program Grant No. 2014CB965001 to JCZ), Joint Research Fund for Overseas Chinese, Hong Kong and Macao Young Scientists of the National Natural Science Foundation of China (No. 81329002 to JCZ), the National Institutes of Health (No. 1R01NS097195-01 to JCZ), the National Natural Science Foundation of China (No. 81901333 to XX), Shanghai Sailing Program (No. 19YF1451700 to XX), China Postdoctoral Science Foundation Grant (No. 2018M642087 to XX), the National Natural Science Foundation of China (No. 81201501 to JZ), the National Natural Science Foundation of China (No. 81801063 to YW), China Postdoctoral Science Foundation Grant (No. 2019M661635 to GG), the National Institute of Mental Health (No. 2P30MH062261 to YH).
Funding Information:
This work was supported in part by research grants from the State Key Program of the National Natural Science Foundation of China (No. 81830037 to JCZ), the National Basic Research Program of China (973 Program Grant No. 2014CB965001 to JCZ), Joint Research Fund for Overseas Chinese, Hong Kong and Macao Young Scientists of the National Natural Science Foundation of China (No. 81329002 to JCZ), the National Institutes of Health (No. 1R01NS097195-01 to JCZ), the National Natural Science Foundation of China (No. 81901333 to XX), Shanghai Sailing Program (No. 19YF1451700 to XX), China Postdoctoral Science Foundation Grant (No. 2018M642087 to XX), the National Natural Science Foundation of China (No. 81201501 to JZ), the National Natural Science Foundation of China (No. 81801063 to YW), China Postdoctoral Science Foundation Grant (No. 2019M661635 to GG), the National Institute of Mental Health (No. 2P30MH062261 to YH).
Publisher Copyright:
© Copyright © 2020 Gao, Li, Zhu, Wang, Huang, Zhao, Sheng, Song, Ji, Li, Yang, Ye, Qi, Zhang, Xia and Zheng.
PY - 2020/2/7
Y1 - 2020/2/7
N2 - 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.
AB - 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.
KW - brain inflammation
KW - exosome
KW - focal cerebral ischemia
KW - glutaminase 1
KW - glutaminase inhibitor
KW - microglial activation
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U2 - 10.3389/fimmu.2020.00161
DO - 10.3389/fimmu.2020.00161
M3 - Article
C2 - 32117296
AN - SCOPUS:85079688042
VL - 11
JO - Frontiers in Immunology
JF - Frontiers in Immunology
SN - 1664-3224
M1 - 161
ER -