Nr4a1调控Th17/Treg平衡抑制溃疡性结肠炎的作用机制

Ulcerative colitis (UC) is a chronic idiopathic inflammatory disorder in the colonic mucosa. The pathogenesis is closely associated with dysfunction of immune response, and the abnormal immune responses of Th17 and Treg cells play key roles in the pathogenesis of UC. Our previous studies have found that an orphan nuclear receptor Nr4a1 markedly improved the T cell induced experimental colitis in mice. Knockout of Nr4a1 could aggravate the colon inflammation in colitis mice. In vitro, an agonist of Nr4a1 (Csn-B) could inhibit the differentiation of Th17 cells from naïve T cells, and increase the differentiation of Treg cells, showing the trends in regulating the balance between Th17 and Treg cells. The project will take advantage of Nr4a1 knockout mice, flow cytometry and transfection methods to investigate the molecular mechanisms of Nr4a1 in regulating the balance between Th17 and Treg cells, and specifically its characteristics on attenuating the experimental UC. Furthermore, we will determine whether Nr4a1 may become a new target toward treating UC effectively. Our findings may contribute a new therapeutic target for drug treatment of UC and other autoimmune diseases.

溃疡性结肠炎（UC）是一种主要累及结肠黏膜的慢性非特异性炎性疾病，发病机制与免疫调节紊乱密切相关，Th17和Treg细胞免疫应答异常在UC病理机制中发挥关键的作用。我们在前期研究中发现，孤儿核受体Nr4a1对T细胞诱导的结肠炎模型小鼠有很好的保护作用，Nr4a1敲除能加重小鼠结肠炎症。体外Nr4a1激动剂（Csn-B）能够抑制Th17细胞分化，促进Treg细胞分化，呈现调控Th17/Treg平衡的趋势。本项目拟从调控Th17/Treg平衡的角度，采用基因敲除、流式细胞术和转染等方法，旨在研究Nr4a1对UC的保护作用特点，探明其调控Th17/Treg平衡的分子机制，并进一步明确Nr4a1是否为干预UC的靶标。本项目有望揭示Nr4a1对UC的保护作用特点及机制，为治疗UC等自身免疫性疾病提供潜在的药物靶点。

溃疡性结肠炎（UC）是一种主要累及结肠黏膜的慢性非特异性炎性疾病，发病机制与免疫调节紊乱密切相关，Th17和Treg细胞免疫应答异常在UC病理机制中发挥关键的作用。孤儿核受体Nr4a1对T细胞诱导的结肠炎小鼠模型和葡聚糖硫酸钠（DSS）复制的结肠炎模型小鼠均有很好的保护作用，敲除Nr4a1能加重小鼠结肠炎症。在结肠炎小鼠模型中，Nr4a1缺失能显著增加结肠LPMC和MLN中Th17细胞比例，降低Treg细胞比例。体外实验中，敲除Nr4a1亦能明显促进Th17细胞分化，减少Treg细胞分化。然而，过表达Nr4a1可抑制Th17细胞分化，Nr4a1激动剂CsnB能够抑制Th17细胞分化，促进Treg细胞分化，表明Nr4a1对Th17/Treg细胞的调控作用。本项目阐明了靶向干预Nr4a1调控Th17/Treg平衡对小鼠UC的作用和特点，揭示了Nr4a1调控结肠炎小鼠的分子机制，为治疗UC等自身免疫性疾病提供潜在的药物靶点。