红景天苷通过STAT3/HIF-1α/RORγt通路调控Th17/Treg平衡治疗再障的机制研究

Acquired aplastic anemia (aplastic anemia, AA) is a seriously life-threatening disease, and its incidence is closely linked to an increase in the number of TH17 cells and a decrease in the number of T regulatory cells (Th17/Treg imbalance). In the early clinical and in vitro studies, our group confirmed that target regulating Th17/treg balance was an effective method for the treatment of AA.Previous studies have shown that hypoxic-induced factor hif-1α can induce Th17 cells differentiation, regulate Th17/Treg equilibrium, and its effect depends on STAT3 signaling pathway. Rhodiola has anti-hypoxia, anti-inflammatory and other effects. Clinical application of Rhodiola to treat AA has obtained good results, but the mechanism of its action is unknown.Previous studies have found that Rhodiola can play a role by inhibiting hif-1α in ischemic and hypoxic diseases such as lung injury and myocardial infarction. So we speculate that Rhodiola may correct the th17/treg imbalance by regulating the stat3/hif-1α/rorγt signaling pathway and inhibiting TH17 differentiation.On the basis of the previous work, this study intends to further study the molecular pathway mechanism of Rhodiola in the treatment of AA, and provide theoretical basis for the treatment AA of Rhodiola.

获得性再生障碍性贫血（aplastic anemia, AA）是严重威胁生命的疾病，其发病与Th17数量增加及Treg数量减少（Th17/Treg平衡失调）密切相关。课题组在前期临床及体外研究中证实，靶向调控Th17/Treg平衡，是治疗AA的有效手段。既往有研究表明，低氧诱导因子HIF-1α可诱导Th17分化，调控Th17/Treg平衡，其作用依赖STAT3信号通路。红景天苷具有抗缺氧、抗炎等作用，临床应用红景天治疗AA获得良好疗效，但作用机制不明。既往研究发现，在肺损伤、心梗等缺血缺氧性疾病中，红景天可通过抑制HIF-1α发挥作用。由此我们推测，红景天苷可能通过调控STAT3/HIF-1α/RORγt信号通路，抑制Th17分化，进而纠正Th17/Treg失衡。本研究拟在前期工作基础上进一步研究红景天苷治疗AA的分子通路机制，为红景天苷治疗AA提供理论依据。

获得性再生障碍性贫血（AA）是一种严重危及生命的疾病，其发病机制中涉及Th17/Treg平衡失调，介导炎症反应的Th17细胞比例上升而具有免疫抑制作用的Treg细胞比例下降。既往研究结果证实，靶向调控Th17/Treg平衡可能是治疗AA的有效方法。近年来研究发现，缺氧诱导因子1α（HIF-1α）可诱导T细胞向Th17细胞分化，在调控Th17/Treg平衡中发挥重要作用。然而，AA患者发病是否涉及HIF-1α高表达尚未见文献报道，有待进一步研究。靶向抑制HIF-1α，理论上可抑制Th17细胞，进而调控Th17/Treg平衡。在中医临床治疗中观察到红景天治疗AA具有良好的疗效，但起效机制尚不清楚，有待进一步探讨。在此，我们首先在临床研究中检测了9例初诊AA患者外周血中HIF-1α的mRNA和蛋白表达，结果发现，与健康对照组相比，AA患者的HIF-1α表达水平明显升高。接下来，我们在AA小鼠模型中使用红景天苷（50mg/kg组及100mg/kg组）灌胃治疗，并与模型小鼠空白组对照，结果证实，红景天苷治疗可改善AA小鼠外周血细胞计数，挽救AA小鼠的骨髓造血功能，具有治疗AA的作用，其中红景天苷100mg/kg组疗效更明显。进一步通过体外细胞实验及动物实验对红景天苷的作用机制进行了研究，结果发现：红景天苷可抑制HIF-1α表达；抑制Th17细胞并上调Treg细胞，调控Th17/Treg平衡。此外，红景天苷可抑制p-JAK2及p-STAT3，提示红景天苷可能通过抑制JAK2/STAT3/HIF-1α/RORγt信号通路，抑制Th17细胞，调控Th17/Treg平衡，发挥治疗AA的作用。