TY - JOUR
T1 - Glycolysis inhibition ameliorates brain injury after ischemic stroke by promoting the function of myeloid-derived suppressor cells
AU - Yan, Jingwei
AU - Li, Anqi
AU - Chen, Xianglin
AU - Cao, Kaixiang
AU - Song, Mingchuan
AU - Guo, Shuai
AU - Li, Zou
AU - Huang, Shuqi
AU - Li, Ziling
AU - Xu, Danghan
AU - Wang, Yong
AU - Dai, Xiaoyan
AU - Feng, Du
AU - Huo, Yuqing
AU - He, Jun
AU - Xu, Yiming
N1 - Funding Information:
This work was supported by grants from the Natural Science Foundation of China (Grant number: 81870217 and 81700395 ), the Key Project of Department of Education of Guangdong Province (Grant number: 2018KZDXM053 ), and American Heart Association (Grant number: 15POST22810024 ). The funders had no contribution to the study design, data collection and analysis, interpretation and writing of the manuscript.
Publisher Copyright:
© 2022 Elsevier Ltd
PY - 2022/5
Y1 - 2022/5
N2 - Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of immature myeloid cells which are immunosuppressive and glycolytically inactive in inflammatory diseases. However, it is unknown whether MDSCs contribute to ischemic stroke and how glycolysis regulates MDSC function in such a context. Here, we showed that MDSCs arise in the blood of patients at early phase of stroke. Similar results were observed in temporary middle cerebral artery occlusion-induced cerebral ischemic mice. Pharmaceutical exhaustion of MDSCs aggravated, while adoptive transfer of MDSCs rescued the ischemic brain injury. However, the differentiation of MDSCs into immunopotent myeloid cells which coincides with increased glycolysis was observed in the context of ischemic stroke. Mechanistically, the glycolytic product lactate autonomously induces MDSC differentiation through activation of mTORC1, and paracrinely activates Th1 and Th17 cells. Moreover, gene knockout or inhibition of the glycolytic enzyme PFKFB3 increased endogenous MDSCs by blocking their differentiation, and improved ischemic brain injury. Collectively, these results revealed that glycolytic switch decreases the immunosuppressive and neuroprotective role of MDSCs in ischemic stroke and pharmacological targeting MDSCs via glycolysis inhibition constitutes a promising therapeutic strategy for ischemic stroke.
AB - Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of immature myeloid cells which are immunosuppressive and glycolytically inactive in inflammatory diseases. However, it is unknown whether MDSCs contribute to ischemic stroke and how glycolysis regulates MDSC function in such a context. Here, we showed that MDSCs arise in the blood of patients at early phase of stroke. Similar results were observed in temporary middle cerebral artery occlusion-induced cerebral ischemic mice. Pharmaceutical exhaustion of MDSCs aggravated, while adoptive transfer of MDSCs rescued the ischemic brain injury. However, the differentiation of MDSCs into immunopotent myeloid cells which coincides with increased glycolysis was observed in the context of ischemic stroke. Mechanistically, the glycolytic product lactate autonomously induces MDSC differentiation through activation of mTORC1, and paracrinely activates Th1 and Th17 cells. Moreover, gene knockout or inhibition of the glycolytic enzyme PFKFB3 increased endogenous MDSCs by blocking their differentiation, and improved ischemic brain injury. Collectively, these results revealed that glycolytic switch decreases the immunosuppressive and neuroprotective role of MDSCs in ischemic stroke and pharmacological targeting MDSCs via glycolysis inhibition constitutes a promising therapeutic strategy for ischemic stroke.
KW - 2,3,5-triphenyltetrazoliium chloride (Pubmed CID: 9283)
KW - 3PO (Pubmed CID: 5720233)
KW - 5-fluorouracil (Pubmed CID: 3385)
KW - Gemcitabine (Pubmed CID: 60750)
KW - Glycolysis
KW - Inflammation
KW - Ischemic stroke
KW - Myeloid-derived suppressor cells
KW - Rapamycin (Pubmed CID: 5284616)
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U2 - 10.1016/j.phrs.2022.106208
DO - 10.1016/j.phrs.2022.106208
M3 - Article
C2 - 35398239
AN - SCOPUS:85129186248
SN - 1043-6618
VL - 179
JO - Pharmacological Research
JF - Pharmacological Research
M1 - 106208
ER -