组蛋白去乙酰化酶Sirt1负性调控调节性T细胞Foxp3表达的分子机制及其在系统性红斑狼疮发病中的作用

The reduced number and deficient immunological suppressive function of regulatory T cells (Tregs) are key factors for the breakdown of immunological self tolerance in systemic lupus erythematosus (SLE). However, their mechanisms remain unclear. The expression of the transcription factor Foxp3 plays essential roles in the maintenance of Tregs numbers and their suppressive function. Our previous studies have demonstrated the overexpression of histone deacetylase Sirt1 in CD4+ T cells from both patients with SLE and MRL/lpr lupus-like mice. Our further experiments revealed that targeted inhibition of Sirt1 in vivo in MRL/lpr lupus-like mice resulted in decreased serum anti-dsDNA antibody level, reduced IgG deposit in kidneys, and amelioration of pathological damage in kidneys, yet its mechanisms remain unknown. Recent studies implied that Sirt1 might have negative regulatory effect on Tregs proliferation and their immunological suppressive function. Based on our previous findings, this project is to investigate the regulation of Foxp3 expression by Sirt1 in Tregs and its molecular mechanisms, and to further examine the roles of Sirt1 overexpression in the proliferative and functional deficiency of Tregs in SLE. This project would help further elucidate the molecular mechanisms of immunological self tolerance breakdown in SLE, and hold potential for new targets and new approaches for treatment of SLE.

调节性T细胞（Treg细胞）数量减少及其免疫抑制功能的缺陷是系统性红斑狼疮（SLE）自身免疫耐受机制破坏的重要因素，然而其原因及发生机制尚不清楚。转录因子Foxp3的表达对维持Treg细胞数量和功能起关键作用。我们的前期研究已证实组蛋白去乙酰化酶Sirt1在SLE患者和MRL/lpr狼疮小鼠的CD4+ T细胞中表达升高；我们发现在MRL/lpr狼疮小鼠体内靶向性抑制Sirt1能降低抗dsDNA抗体水平及肾脏IgG沉积，减轻肾脏病理损害，但其具体机制不明。近年研究提示Sirt1可能对Treg细胞数量和功能具有负性调控作用。本项目拟在前期研究基础上，探讨Sirt1对外周血Treg细胞Foxp3表达的调控及其分子机制，进一步揭示Sirt1过度表达在SLE患者Treg细胞数量及其免疫抑制功能缺陷中的作用。本研究将有助于进一步阐明SLE自身免疫耐受破坏的分子机制，可能为SLE治疗提供新的靶点和途径。

系统性红斑狼疮（SLE）是一种累及多器官、多系统的自身免疫性疾病，其发病机制至今尚不十分清楚，现有的治疗药物以糖皮质激素、免疫抑制剂为主，具有较明显的毒副作用。近年来研究发现，调节性T细胞（Treg）和Th17细胞分别具有抑制炎症反应和促炎的作用，二者的相互作用和动态平衡在自身免疫性疾病的发病机制中可能具有重要作用。我们的前期研究发现组蛋白去乙酰化酶Sirt1在SLE患者和MRL/lpr 狼疮小鼠的CD4+ T细胞中表达升高；在MRL/lpr 狼疮小鼠体内靶向性抑制Sirt1能降低抗dsDNA抗体水平及肾脏IgG沉积，减轻肾脏病理损害，但其具体机制不明。本项目通过体外实验和动物体内实验，证实了Sirt1在系统性红斑狼疮患者外周血调节性T细胞（Treg）中表达升高，但发现Sirt1对Treg细胞及其关键分子Foxp3的表达并无显著调控作用；同时，本项目发现一种低毒副作用的Sirt1抑制剂——烟酰胺，在体外和体内均可显著抑制Th17细胞，从而调节Treg/Th17之间的平衡，并且在MRL/lpr狼疮小鼠模型中证实其对血清自身抗体（抗dsDNA）水平、尿蛋白、肾脏病理损害及免疫复合物沉积、皮肤损害以及病死率等方面均有显著改善。本项目还发现传统中药提取物水合淫羊藿素也可调节Treg/Th17平衡并对MRL/lpr狼疮小鼠的肾损害具有保护作用。本项目研究结果提示Sirt1可能通过诱发Treg/Th17失衡参与SLE发病机制，并有望为SLE的治疗带来低毒副作用的新选择。本项目后续还将通过更大样本、更多不同类型SLE动物模型对上述药物的疗效进行验证，更深入探讨其分子机制，以及开展相关的临床试验来证实其治疗价值。