Thymopentin ameliorates dextran sulfate sodium-induced colitis by triggering the production of IL-22 in both innate and adaptive lymphocytes
Thymopentin ameliorates dextran sulfate sodium-induced colitis by triggering the production of IL-22 in both innate and adaptive lymphocytes
复制标题
胸腺五肽通过触发先天性和适应性淋巴细胞中 IL-22 的产生来改善葡聚糖硫酸钠诱导的结肠炎
DOI：
10.7150/thno.35015
复制
发表时间：
2019-01-01
期刊：
影响因子：
12.4
通讯作者：
Yang, Yong
中科院分区：
文献类型：
--
作者：
Cao, Qiuhua;Gao, Xinghua;Yang, Yong
背景：溃疡性结肠炎（UC）是一种慢性炎症性胃肠道疾病，治疗起来非常困难。先前的研究发现胸腺萎缩与结肠炎严重程度呈正相关。因此，值得研究胸腺五肽（TP5）（一种与胸腺生成素活性结构域相对应的合成五肽）对结肠炎的作用。方法：皮下注射TP5治疗右旋糖酐硫酸钠（DSS）诱导的结肠炎小鼠。检查体重、结肠长度、结肠重量、免疫器官指数、疾病活动指数（DAI）评分和外周血谱。通过流式细胞术分析脾脏和结肠的免疫细胞。对分离的结肠组织进行组织学分析以进行细胞因子分析。从小鼠结肠粪便中提取细菌 DNA 以评估肠道微生物群。培养肠固有层单核细胞 (LPMC)、HCT116、CT26 和脾细胞，并用 TP5 处理。结果：TP5 治疗增加了结肠炎小鼠的体重和结肠长度，降低了 DAI 评分，并恢复了结肠结构。 TP5 还降低了免疫细胞的浸润和促炎细胞因子（如 IL-6）的表达水平。重要的是，TP5显着修复了受损的胸腺和外周血中受损的淋巴细胞。此外，先天性和适应性淋巴细胞中 IL-22 的产生都是由 TP5 触发的。鉴于IL-22在粘膜宿主防御中的关键作用，我们测试了TP5对粘液屏障和肠道微生物群的影响，发现TP5治疗后杯状细胞的数量和Mucin-2表达水平得到恢复，肠道微生物组的组成恢复正常。通过施用抗IL-22抗体（αIL-22）进一步证实了IL-22在TP5对结肠炎的保护作用中的关键作用，该抗体完全消除了TP5的作用。此外，TP5 显着增加视黄酸受体相关孤儿受体 γ (RORγt)（IL-22 的转录因子）的表达水平。与此一致的是，RORγt 抑制剂消除了 TP5 诱导的 IL-22 上调。结论：TP5 通过触发先天性和适应性淋巴细胞产生 IL-22，对 DSS 诱导的结肠炎发挥保护作用。这项研究将 TP5 描述为一种免疫调节剂，可能成为治疗 UC 的潜在药物。
Background: Ulcerative colitis (UC) is a chronic inflammatory gastrointestinal disease, notoriously challenging to treat. Previous studies have found a positive correlation between thymic atrophy and colitis severity. It was, therefore, worthwhile to investigate the effect of thymopentin (TP5), a synthetic pentapeptide corresponding to the active domain of the thymopoietin, on colitis. Methods: Dextran sulfate sodium (DSS)-induced colitis mice were treated with TP5 by subcutaneous injection. Body weight, colon length, colon weight, immune organ index, disease activity index (DAI) score, and the peripheral blood profile were examined. The immune cells of the spleen and colon were analyzed by flow cytometry. Histology was performed on isolated colon tissues for cytokine analysis. Bacterial DNA was extracted from mouse colonic feces to assess the intestinal microbiota. Intestinal lamina propria mononuclear cells (LPMCs), HCT116, CT26, and splenocytes were cultured and treated with TP5. Results: TP5 treatment increased the body weight and colon length, decreased the DAI score, and restored colon architecture of colitic mice. TP5 also decreased the infiltration of immune cells and expression levels of pro-inflammatory cytokines such as IL-6. Importantly, the damaged thymus and compromised lymphocytes in peripheral blood were significantly restored by TP5. Also, the production of IL-22, both in innate and adaptive lymphoid cells, was triggered by TP5. Given the critical role of IL-22 in mucosal host defense, we tested the effect of TP5 on mucus barrier and gut microbiota and found that the number of goblet cells and the level of Mucin-2 expression were restored, and the composition of the gut microbiome was normalized after TP5 treatment. The critical role of IL-22 in the protective effect of TP5 on colitis was further confirmed by administering the anti-IL-22 antibody (αIL-22), which completely abolished the effect of TP5. Furthermore, TP5 significantly increased the expression level of retinoic acid receptor-related orphan receptor γ (RORγt), a transcription factor for IL-22. Consistent with this, RORγt inhibitor abrogated the upregulation of IL-22 induced by TP5. Conclusion: TP5 exerts a protective effect on DSS-induced colitis by triggering the production of IL-22 in both innate and adaptive lymphocytes. This study delineates TP5 as an immunomodulator that may be a potential drug for the treatment of UC.