Wang Huiling, Chao Kang, Ng Siew Chien, Bai Alfa Hc, Yu Qiao, Yu Jun, Li Manying, Cui Yi, Chen Minhu, Hu Ji-Fan, Zhang Shenghong
Division of Gastroenterology, The First Affiliated Hospital, Sun Yat-sen University, No. 58, Zhongshan Road 2, Guangzhou, 510080, P.R. China.
Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Institute of Digestive Disease, Li Ka Shing Institute of Health Science, Hong Kong, P.R. China.
Genome Biol. 2016 Mar 30;17:58. doi: 10.1186/s13059-016-0901-8.
The IL23/Th17 pathway is essential for the onset of inflammatory bowel disease (IBD), yet the specific mechanism by which this pathway initiates the disease remains unknown. In this study, we identify the mechanisms that mediate cross-talk between the IL23 pathway and the intestinal barrier in IBD.
The downstream targets of the IL23 pathway were identified by RNA array profiling and confirmed by immunohistochemical staining. The role of miRNAs that interact with IL23 was explored in mice with TNBS-induced colitis. Claudin-8 (CLDN8), a multigene family protein that constitutes the backbone of tight junctions, was identified as a novel target of IL23 in IBD. CLDN8 was significantly downregulated in IBD patients with inflamed colonic mucosa, and in trinitrobenzene sulphonic acid (TNBS) induced colitis in mice. Therapeutic treatment of colitis in mice using an IL23 antibody restored CLDN8 abundance, in parallel with recovery from colitis. In addition, we identify miR-223 as a novel mediator of the crosstalk between the IL23 signal pathway and CLDN8 in the development of IBD. MiR-223 was upregulated in IBD, and its activity was regulated through the IL23 pathway. Antagomir inhibition of miR-223 reactivated CLDN8 and improved a number of signs associated with TNBS-induced colitis in mice.
Our study characterizes a new mechanistic pathway in IBD, in which miR-223 interacts with the IL23 pathway by targeting CLDN8. Strategies designed to disrupt this interaction may provide novel therapeutic agents for the management of IBD.
白细胞介素23（IL23）/辅助性T细胞17（Th17）通路对于炎症性肠病（IBD）的发病至关重要，但该通路引发疾病的具体机制仍不清楚。在本研究中，我们确定了IBD中IL23通路与肠道屏障之间介导相互作用的机制。
通过RNA阵列分析确定了IL23通路的下游靶点，并通过免疫组织化学染色进行了验证。在三硝基苯磺酸（TNBS）诱导的结肠炎小鼠中探索了与IL23相互作用的微小RNA（miRNA）的作用。Claudin-8（CLDN8）是构成紧密连接骨架的多基因家族蛋白，被确定为IBD中IL23的新靶点。CLDN8在患有炎症性结肠黏膜的IBD患者以及TNBS诱导的小鼠结肠炎中显著下调。使用IL23抗体对小鼠结肠炎进行治疗性处理可恢复CLDN8丰度，同时结肠炎也得以恢复。此外，我们确定miR-223是IBD发展过程中IL23信号通路与CLDN8之间相互作用的新介质。miR-223在IBD中上调，其活性通过IL23通路调节。对miR-223进行反义寡核苷酸抑制可重新激活CLDN8，并改善与TNBS诱导的小鼠结肠炎相关的一些症状。
我们的研究描述了IBD中的一种新机制途径，其中miR-223通过靶向CLDN8与IL23通路相互作用。旨在破坏这种相互作用的策略可能为IBD的治疗提供新的治疗药物。
