Glycolysis inhibition ameliorates brain injury after ischemic stroke by promoting the function of myeloid-derived suppressor cells.
2,3,5-triphenyltetrazoliium chloride (Pubmed CID: 9283)
3PO (Pubmed CID: 5720233)
5-fluorouracil (Pubmed CID: 3385)
Gemcitabine (Pubmed CID: 60750)
Glycolysis
Inflammation
Ischemic stroke
Myeloid-derived suppressor cells
Rapamycin (Pubmed CID: 5284616)
Journal
Pharmacological research
ISSN: 1096-1186
Titre abrégé: Pharmacol Res
Pays: Netherlands
ID NLM: 8907422
Informations de publication
Date de publication:
05 2022
05 2022
Historique:
received:
10
01
2022
revised:
31
03
2022
accepted:
03
04
2022
pubmed:
11
4
2022
medline:
25
5
2022
entrez:
10
4
2022
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 35398239
pii: S1043-6618(22)00153-0
doi: 10.1016/j.phrs.2022.106208
pmc: PMC10364470
mid: NIHMS1909087
pii:
doi:
Substances chimiques
Immunosuppressive Agents
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
106208Subventions
Organisme : NHLBI NIH HHS
ID : R01 HL134934
Pays : United States
Informations de copyright
Copyright © 2022 Elsevier Ltd. All rights reserved.
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