Journal
PHARMACOLOGICAL RESEARCH
Volume 179, Issue -, Pages -Publisher
ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD
DOI: 10.1016/j.phrs.2022.106208
Keywords
Myeloid-derived suppressor cells; Glycolysis; Inflammation; Ischemic stroke
Categories
Funding
- Natural Science Foundation of China [81870217, 81700395]
- Key Project of Department of Education of Guangdong Province [2018KZDXM053]
- American Heart Association [15POST22810024]
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The study found that MDSCs appear in the blood of stroke patients in the early stage, and similar results were observed in a rat brain model induced by temporary middle cerebral artery occlusion. The research showed that pharmaceutical depletion of MDSCs worsens ischemic brain injury, while adoptive transfer of MDSCs can rescue the damage.
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 Thl 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.
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