Department of Gastroenterology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, Jiangsu, China.
Inflammation. 2020 Oct;43(5):1862-1875. doi: 10.1007/s10753-020-01259-0.
Growing evidence suggested that microRNAs (miRNAs) contributed to the progression of Crohn's disease (CD), but the exact physiological functions of many miRNAs in CD patients still remain illusive. In this study, we explore the potent pathogenicity of miRNAs in CD. Expressions of miRNAs and aryl hydrocarbon receptor (AHR) protein were determined in the colitic colon of 2,4,6-trinitrobenzenesulfonic acid (TNBS)-induced colitis mice and CD patients. Colitis was induced in wild-type (WT), miR-124a overexpression (miR-124a-Nju), and AHR knockout (AHR) mice. Intestinal barrier function was evaluated in colitis mice and Caco2 monolayers. There was a negative relationship between miR-124a and AHR protein in inflamed colons from CD patients. MiR-124a-Nju and AHR mice treated with TNBS had more severe intestinal inflammation than WT mice. Both miR-124a-Nju mice and AHR mice underwent evident intestinal barrier destruction, and anti-miR-124a administration could reverse this dysfunction in miR-124a-Nju mice but not in AHR mice. In vitro studies revealed that miR-124a mimics downregulated the expression of AHR and tight junction proteins and induced hyperpermeability by increasing miR-124a expression, which was abrogated by miR-124a inhibitor and AHR antagonist FICZ. This study suggests that miR-124a can induce intestinal inflammation and cause intestinal barrier dysfunction by supressing AHR.
越来越多的证据表明 microRNAs（miRNAs）参与了克罗恩病（CD）的进展，但许多 miRNA 在 CD 患者中的确切生理功能仍不清楚。在这项研究中，我们探讨了 miRNAs 在 CD 中的潜在致病性。在 2,4,6-三硝基苯磺酸（TNBS）诱导的结肠炎小鼠和 CD 患者的结肠中测定了 miRNAs 和芳香烃受体（AHR）蛋白的表达。在野生型（WT）、miR-124a 过表达（miR-124a-Nju）和 AHR 敲除（AHR）小鼠中诱导结肠炎。在结肠炎小鼠和 Caco2 单层中评估肠道屏障功能。在 CD 患者的炎症结肠中，miR-124a 与 AHR 蛋白之间存在负相关。与 WT 小鼠相比，用 TNBS 处理的 miR-124a-Nju 和 AHR 小鼠具有更严重的肠道炎症。miR-124a-Nju 小鼠和 AHR 小鼠均发生明显的肠道屏障破坏，抗 miR-124a 给药可逆转 miR-124a-Nju 小鼠但不能逆转 AHR 小鼠的这种功能障碍。体外研究表明，miR-124a 模拟物通过下调 AHR 和紧密连接蛋白的表达并通过增加 miR-124a 的表达诱导高通透性，miR-124a 抑制剂和 AHR 拮抗剂 FICZ 可阻断这种作用。这项研究表明，miR-124a 可以通过抑制 AHR 诱导肠道炎症并导致肠道屏障功能障碍。
