Glycolysis inhibition ameliorates brain injury after ischemic stroke by promoting the function of myeloid-derived suppressor cells.
Glycolysis inhibition ameliorates brain injury after ischemic stroke by promoting the function of myeloid-derived suppressor cells.
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糖酵解抑制通过促进髓系抑制细胞的功能来改善缺血性卒中后的脑损伤。
DOI：
10.1016/j.phrs.2022.106208
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发表时间：
2022-04
影响因子：
9.3
通讯作者：
Jian Yan;Anqi Li;Xianglin Chen;Kaixiang Cao;Mingchuan Song;Shuai Guo;Zou Li;Shuqi Huang;Ziling Li;Danghan Xu;Yong Wang;Xiao-Ping Dai;Du Feng;Yuqing Huo;Jun He;Yiming Xu
中科院分区：
文献类型：
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作者：
Jian Yan;Anqi Li;Xianglin Chen;Kaixiang Cao;Mingchuan Song;Shuai Guo;Zou Li;Shuqi Huang;Ziling Li;Danghan Xu;Yong Wang;Xiao-Ping Dai;Du Feng;Yuqing Huo;Jun He;Yiming Xu
髓源性抑制细胞（myeloid -derived suppressor cells, MDSCs）是一种异质的未成熟髓细胞群，在炎症性疾病中具有免疫抑制和糖酵解活性。然而，目前尚不清楚MDSCs是否有助于缺血性中风，以及糖酵解如何调节MDSC在这种情况下的功能。在这里，我们发现MDSCs出现在中风早期患者的血液中。在大脑中动脉暂时性闭塞引起的脑缺血小鼠中也观察到类似的结果。MDSCs药物耗竭加重，而MDSCs过继性转移可挽救缺血性脑损伤。然而，在缺血性中风的情况下，观察到MDSCs分化为具有免疫能力的髓细胞，与糖酵解增加相一致。机制上，糖酵解产物乳酸通过激活mTORC1自主诱导MDSC分化，并旁分泌激活Th1和Th17细胞。此外，基因敲除或抑制糖酵解酶PFKFB3通过阻断内源性MDSCs的分化而增加，并改善缺血性脑损伤。综上所述，这些结果表明糖酵解开关降低了MDSCs在缺血性卒中中的免疫抑制和神经保护作用，通过糖酵解抑制药物靶向MDSCs是一种很有前景的缺血性卒中治疗策略。
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.