Department of Gastroenterology, Zhongnan Hospital of Wuhan University, Wuhan, China.
The Hubei Clinical Center & Key Laboratory of Intestinal & Colorectal Diseases, Wuhan, China.
Front Immunol. 2020 May 28;11:852. doi: 10.3389/fimmu.2020.00852. eCollection 2020.
This study aimed to investigate long-non-coding RNA (lncRNA) expression profiles and the correlation of lnc-ITSN1-2 expression with disease risk, activity and inflammation, and its influence on CD4 T cell activation, proliferation, and differentiation of inflammatory bowel disease (IBD). LncRNA expression profiles were detected in intestinal mucosa samples from six IBD patients and six healthy controls (HCs). Intestinal mucosa and PBMC lnc-ITSN1-2, IL-23R, and inflammatory cytokines were measured in 120 IBD patients [60 Crohn's disease (CD) and 60 ulcerative colitis (UC)] and 30 HCs. Effect of lnc-ITSN1-2 on IBD CD4 T cell activation, proliferation, and differentiation was determined and its regulatory interaction with miR-125a and IL-23R was detected. Three-hundred-and-nine upregulated and 310 downregulated lncRNAs were identified in IBD patients by RNA-Sequencing, which were enriched in regulating immune and inflammation related pathways. Large-sample qPCR validation disclosed that both intestinal mucosa and PBMC lnc-ITSN1-2 expressions were increased in IBD patients compared to HCs, and presented with good predictive values for IBD risk, especially for active disease conditions, and they positively correlated with disease activity, inflammation cytokines, and IL-23R in IBD patients. Lnc-ITSN1-2 was decreased after infliximab treatment in active-CD patients. Furthermore, lnc-ITSN1-2 promoted IBD CD4 T cell activation and proliferation, and stimulated Th1/Th17 cell differentiation. Multiple rescue experiments disclosed that lnc-ITSN1-2 functioned in IBD CD4 T cells via targeting miR-125a, then positively regulating IL-23R. Luciferase Reporter assay observed that lnc-ITSN1-2 bound miR-125a, and miR-125a bound IL-23R. Lnc-ITSN1-2 correlates with increased disease risk, activity, and inflammatory cytokines of IBD, and promotes IBD CD4 T cell activation, proliferation, and Th1/Th17 cell differentiation by serving as a competing endogenous RNA for IL-23R via sponging miR-125a.
本研究旨在探讨长链非编码 RNA（lncRNA）表达谱以及 lnc-ITSN1-2 表达与疾病风险、活动和炎症的相关性，并研究其对炎症性肠病（IBD）中 CD4 T 细胞活化、增殖和分化的影响。本研究检测了 6 例 IBD 患者和 6 例健康对照者（HC）肠道黏膜样本中的 lncRNA 表达谱。检测了 120 例 IBD 患者[60 例克罗恩病（CD）和 60 例溃疡性结肠炎（UC）]和 30 例 HCs 肠道黏膜和 PBMC 中 lnc-ITSN1-2、IL-23R 和炎症细胞因子。并确定了 lnc-ITSN1-2 对 IBD CD4 T 细胞活化、增殖和分化的影响，并检测了其与 miR-125a 和 IL-23R 的调控相互作用。通过 RNA 测序鉴定了 IBD 患者 339 个上调和 310 个下调的 lncRNA，这些 lncRNA在调节免疫和炎症相关途径中富集。大样本 qPCR 验证显示，与 HCs 相比，IBD 患者肠道黏膜和 PBMC 中的 lnc-ITSN1-2 表达均增加，对 IBD 风险具有良好的预测价值，特别是对活动性疾病，且与 IBD 患者的疾病活动度、炎症细胞因子和 IL-23R 呈正相关。在活动期 CD 患者中，英夫利昔单抗治疗后 lnc-ITSN1-2 表达降低。此外，lnc-ITSN1-2 促进 IBD CD4 T 细胞的活化和增殖，并刺激 Th1/Th17 细胞分化。多项挽救实验显示，lnc-ITSN1-2 通过靶向 miR-125a 作用于 IBD CD4 T 细胞，然后正向调节 IL-23R。荧光素酶报告试验观察到 lnc-ITSN1-2 与 miR-125a 结合，miR-125a 与 IL-23R 结合。lnc-ITSN1-2 与 IBD 疾病风险、活动度和炎症细胞因子的增加相关，通过作为 IL-23R 的竞争性内源性 RNA 来发挥作用，通过海绵吸附 miR-125a 来促进 IBD CD4 T 细胞的活化、增殖和 Th1/Th17 细胞分化。
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