RAGE调控CD4+T细胞ACC1酶在加重脑缺血再灌注损伤中的作用与机制

脑卒中恢复血运后的再灌注损伤对卒中后神经功能恢复有重要影响，然尚无有效治疗手段。文献及申请人的研究均提示CD4+Treg对脑缺血再灌注损伤有保护作用, 而其在早期数量有所减少。本课题通过RNA测序发现脑卒中后CD4+T细胞内IL-17通路表达显著上调, 提示Th17细胞分化增强。由于CD4+Treg及Th17细胞均可由幼稚型CD4+T细胞分化而来, 而乙酰辅酶A羧化酶1（ACC1）是调控其分化的关键酶，因此提出假说：脑卒中后，幼稚型CD4+T细胞受缺血危险信号激活,其表面RAGE受体介导CD4+T细胞内的ACC1表达上调, 从而诱导幼稚型CD4+T细胞向Th17分化并阻碍其向Treg细胞的分化, 加重脑缺血再灌注损伤后神经炎症反应。本研究拟应用流式细胞分选，条件性基因敲除，细胞代谢分析等手段来证明上述假说，以期为脑缺血再灌注后的神经炎症反应找到新的机制及提出新的治疗靶点。

Cerebral ischemic and reperfusion injury after revascularization has detrimental impacts on stroke recovery with limited transitional success of mounting stroke researches, posing an economic and societal burden. Both the literature and our preliminary studies suggest that CD4+ Tregs have protective effects on cerebral ischemia-reperfusion injury, but the number of CD4+ Tregs decrease early after stroke. In this study, RNA sequencing of CD4+ T cells after stroke showed that the expression of IL-17 pathway was significantly up-regulated, suggesting enhanced differentiation of Th17 cells. Since both CD4+Tregs and Th17 cells can be differentiated from immature CD4+T cells, and acetyl coenzyme A carboxylase 1 (ACC1), the key enzyme for fatty acid synthesis, is the rate-limiting enzyme regulating their differentiation, we hypothesize that immature CD4+T cells are activated by ischemic risk signals via the receptor for advanced glycation end products（RAGE), leading to upregulated ACC1 expression in CD4+T cells, which induces enhanced differentiation of immature CD4+T cells into Th17 cell, reducing the Treg numbers after stroke and aggravates neuroinflammation after cerebral ischemia-reperfusion injury. In this study, conditional knockout of ACC1 and flow sorting of CD4+ T cells were used to address the above hypothesis, in the pursuit of discovering new mechanisms and developing innovative therapeutic targets of neuroinflammation after cerebral ischemic and reperfusion injury.