基于调控脂代谢限速酶修复Th17/Treg细胞失衡探讨羟氯喹治疗系统性红斑狼疮的机制研究

Abnormal lipid metabolism and Th17/Treg functional imbalance play an important role in the development of systemic lupus erythematosus (SLE). Hydroxychloroquine is a first-line drug in SLE treatment, and it has been confirmed that it has the dual role of regulating Th17/Treg balance and improving lipid metabolism, but the specific mechanism has not been reported yet. In the early stage, it was found that hydroxychloroquine could significantly improve the abnormal lipid metabolism and repair the imbalance of Th17/Treg function. Speed limit fat synthesis enzyme acetyl-coa carboxylase 1 (ACC1) is the key to affect the balance of Th17 / Treg metabolic targets, metabonomics analysis found that hydroxychloroquine ACC1 influence of liver cell is the most significant, so we speculated that hydroxychloroquine may through regulating liver and ACC1 of Th17 / Treg cells, improve SLE abnormal lipid metabolism, repair of Th17 / Treg imbalance, improve SLE condition and prognosis. This project proposed by animal studies in vivo and in vitro and SLE patients with peripheral blood T cells in vitro induced, ACC1 in hydroxychloroquine improve SLE of Th17 / Treg function imbalance, have important mediating role for SLE metabolism immune treatment strategies to provide new ideas and methods, to better treatment and prevention of SLE provides new theoretical support.

脂代谢异常和Th17/Treg功能失衡在系统性红斑狼疮(SLE)的发生发展中均有重要作用。羟氯喹是SLE治疗的一线药物，已有研究证实其具有调节Th17/Treg平衡和改善脂代谢的双重作用，但具体机制尚无报道。前期利用狼疮鼠模型发现：羟氯喹可以明显改善其脂代谢异常，修复Th17/Treg功能失衡。脂肪合成限速酶乙酰辅酶A羧化酶1(ACC1)是影响Th17/Treg平衡的关键代谢靶点，代谢组学分析发现羟氯喹对肝细胞ACC1影响最显著，故我们推测羟氯喹可通过调控肝脏和Th17/Treg细胞的ACC1，改善SLE脂代谢异常，修复Th17/Treg失衡，改善SLE病情及预后。本项目拟通过动物体内外研究及SLE患者外周血T细胞体外诱导，阐明ACC1在羟氯喹改善SLE的Th17/Treg功能失衡中有重要介导作用，为SLE的代谢免疫治疗策略提供新的思路和方法，为更好地治疗和预防SLE提供新的理论支持。

脂代谢异常和T细胞功能失衡在系统性红斑狼疮(SLE)的发生发展中均有重要作用。羟氯喹是SLE治疗的一线药物，已有研究证实其具有调节免疫和改善脂代谢的双重作用， 本项目初步阐明脂肪酸合成限速酶ACC1在HCQ调控代谢的重要作用; 明确ACC1参与介导HCQ对脂代谢的作用，并深入探讨了其具体机制,找到其潜在作用靶点，发表相关SCI论文1篇，培养硕士研究生1名。托法替布是一种新兴的小分子免疫抑制剂，近年来开始广泛应用于风湿病的临床治疗，但该药物增加胆固醇水平，且增加了血栓的风险。为了进一步评估托法替布对肝脏脂肪代谢的影响，本课题组制造CIA模型鼠，通过不同剂量的托法替布干预后，明确该药物对肝脏脂代谢的影响并进一步找寻其可能的作用靶点。这一成果准备撰写SCI论文1篇，培养硕士研究生1名。这一成果为临床该药物的应用提供更多的理论依据，更好的改善风湿病患者的预后。随着氧固醇参与免疫调控研究的深入，其是否参与SLE的发生发展引起了我们极大的兴趣。为了进一步了解其对SLE免疫细胞功能的调节作用，本课题组应用用LC-MS检测SLE患者氧固醇水平，同时检测胆固醇代谢相关配体的表达水平，初步验证了我们的假设，即SLE患者T细胞胆固醇代谢异常导致其功能异常，并将进一步在后续更深入地研究，为SLE的代谢免疫治疗策略提供新的思路和方法，为更好地治疗和预防SLE提供新的理论支持。