Wu Hua, Li Xiu-Ming, Wang Jing-Ru, Gan Wen-Juan, Jiang Fu-Quan, Liu Yao, Zhang Xin-Dao, He Xiao-Shun, Zhao Yuan-Yuan, Lu Xing-Xing, Guo Yan-Bing, Zhang Xiao-Kun, Li Jian-Ming
Pathology Centre and Department of Pathology, Soochow University, Suzhou, People's Republic of China.
First Affiliated Hospital of Soochow University, Suzhou, People's Republic of China.
J Pathol. 2016 Feb;238(3):457-69. doi: 10.1002/path.4670. Epub 2015 Dec 21.
Nur77, an immediate-early response gene, participates in a wide range of biological functions. Its human homologue, NUR77, is known by several names and has the HGNC-approved gene symbol NR4A1. However, the role of Nur77 in inflammatory bowel disease (IBD) and its underlying mechanisms remain elusive. Here, using public data from the International Inflammatory Bowel Disease Genetics Consortium (IIBDGC) on the most recent genome-wide association studies (GWAS) for ulcerative colitis (UC) and Crohn's disease (CD), we found that genetic variants of the NUR77 gene are associated with increased risk for both UC and CD. Accordingly, Nur77 expression was significantly reduced in colon tissues from patients with UC or CD and mice treated with DSS. Nur77 deficiency increased the susceptibility of mice to DSS-induced experimental colitis and prevented intestinal recovery, whereas treatment with cytosporone B (Csn-B), an agonist for Nur77, significantly attenuated excessive inflammatory response in the DSS-induced colitis mouse model. Mechanistically, NUR77 acts as a negative regulator of TLR-IL-1R signalling by interacting with TRAF6. This interaction prevented auto-ubiquitination and oligomerization of TRAF6 and subsequently inhibited NF-κB activation and pro-inflammatory cytokine production. Taken together, our GWAS-based analysis and in vitro and in vivo studies have demonstrated that Nur77 is an important regulator of TRAF6/TLR-IL-1R-initiated inflammatory signalling, and loss of Nur77 may contribute to the development of IBD, suggesting Nur77 as a potential target for the prevention and treatment of IBD.
Nur77是一种立即早期反应基因，参与多种生物学功能。其人类同源物NUR77有多个名称，并且具有HGNC批准的基因符号NR4A1。然而，Nur77在炎症性肠病（IBD）中的作用及其潜在机制仍不清楚。在这里，我们使用来自国际炎症性肠病遗传学联盟（IIBDGC）的关于溃疡性结肠炎（UC）和克罗恩病（CD）的最新全基因组关联研究（GWAS）的公共数据，发现NUR77基因的遗传变异与UC和CD的患病风险增加相关。相应地，在UC或CD患者以及用葡聚糖硫酸钠（DSS）处理的小鼠的结肠组织中，Nur77表达显著降低。Nur77缺陷增加了小鼠对DSS诱导的实验性结肠炎的易感性，并阻碍肠道恢复，而用Nur77激动剂环孢菌素B（Csn - B）治疗可显著减轻DSS诱导的结肠炎小鼠模型中的过度炎症反应。机制上，NUR77通过与肿瘤坏死因子受体相关因子6（TRAF6）相互作用，作为Toll样受体 - 白细胞介素 - 1受体（TLR - IL - 1R）信号通路的负调节因子。这种相互作用阻止了TRAF6的自身泛素化和寡聚化，随后抑制了核因子κB（NF - κB）的激活和促炎细胞因子的产生。综上所述，我们基于GWAS的分析以及体外和体内研究表明，Nur77是TRAF6/TLR - IL - 1R启动的炎症信号的重要调节因子，Nur77的缺失可能导致IBD的发生，提示Nur77作为IBD预防和治疗的潜在靶点。
