Pro-inflammatory miR-223 mediates the cross-talk between the IL23 pathway and the intestinal barrier in inflammatory bowel disease.
Pro-inflammatory miR-223 mediates the cross-talk between the IL23 pathway and the intestinal barrier in inflammatory bowel disease.
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促炎性 miR-223 介导炎症性肠病中 IL23 通路与肠道屏障之间的串扰
DOI：
10.1186/s13059-016-0901-8
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发表时间：
2016-03-30
期刊：
影响因子：
12.3
通讯作者：
Zhang S
中科院分区：
文献类型：
--
作者：
Wang H;Chao K;Ng SC;Bai AH;Yu Q;Yu J;Li M;Cui Y;Chen M;Hu JF;Zhang S
IL23/Th17通路在炎症性肠病(IBD)的发病中起着至关重要的作用，但该通路引发IBD的具体机制尚不清楚。在本研究中，我们确定了IL-23途径与IBD肠道屏障之间的串扰机制。结果通过RNA阵列分析确定了IL-23途径的下游靶点，并经免疫组织化学染色证实。在TNBS诱导的结肠炎小鼠中，探索了与IL23相互作用的miRNAs的作用。Claudin-8(CLDN8)是构成紧密连接骨架的多基因家族蛋白，被认为是IBD中IL23的新靶点。CLDN8在炎症性肠病患者和三硝基苯磺酸(TNBS)诱导的小鼠结肠炎中表达显著下调。在治疗结肠炎的同时，使用IL23抗体治疗小鼠的结肠炎恢复了CLDN8的丰度。此外，我们发现miR-223在IBD的发生发展中是IL23信号通路与CLDN8之间串扰的一个新的介导者。MIR-223在IBD中表达上调，其活性通过IL23途径调节。抑制miR-223可重新激活CLDN8，并改善与TNBS诱导的小鼠结肠炎相关的一些体征。结论我们的研究揭示了IBD的一种新的机制途径，即miR-223通过靶向CLDN8与IL23途径相互作用。旨在破坏这种相互作用的策略可能会为IBD的治疗提供新的治疗剂。
BackgroundThe 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.ResultsThe 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.ConclusionsOur 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.