Th17 Cell-Derived Amphiregulin Promotes Colitis-Associated Intestinal Fibrosis Through Activation of mTOR and MEK in Intestinal Myofibroblasts.
Th17 Cell-Derived Amphiregulin Promotes Colitis-Associated Intestinal Fibrosis Through Activation of mTOR and MEK in Intestinal Myofibroblasts.
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Th17 细胞衍生的双调蛋白通过激活肠肌成纤维细胞中的 mTOR 和 MEK 促进结肠炎相关的肠纤维化。
DOI：
10.1053/j.gastro.2022.09.006
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发表时间：
2023
期刊：
影响因子：
29.4
通讯作者：
中科院分区：
文献类型：
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作者：
Zhao,Xiaojing;Yang,Wenjing;Yu,Tianming;Yu,Yu;Cui,Xiufang;Zhou,Zheng;Yang,Hui;Yu,Yanbo;Bilotta,AnthonyJ;Yao,Suxia;Xu,Jimin;Zhou,Jia;Yochum,GregoryS;Koltun,WalterA;Portolese,Austin;Zeng,Defu;Xie,Jingwu;Pinchuk,IrynaV;
背景与目的肾间质纤维化是克罗恩病(CD)的重要并发症。肠道微生物区系反应性Th17细胞在CD的发病机制中起重要作用，但Th17细胞诱导肠纤维化的机制尚不完全清楚。方法采用野生型(WT)T细胞转移模型，−/−Th17细胞和葡聚糖硫酸钠(DSS)诱导的WT和ARG−/−小鼠慢性结肠炎模型。用定量逆转录聚合酶链式反应和酶联免疫吸附试验检测AREG中CD4+T细胞的表达。观察AREG对人肠肌成纤维细胞增殖/迁移/胶原表达的影响。结果尽管Th1和Th17细胞在Tcrβxδ−/−小鼠体内诱导的肠道炎症程度相似，但Th17细胞诱导的肠纤维化程度更严重。Th17细胞表达AREG的水平高于Th1细胞。与WT小鼠相比，−/−小鼠在DSS侮辱条件下出现较轻的肠纤维化。与WT Th17细胞相比，转移ARG−/−Th17细胞对Tcrβxδ−/−小鼠的纤维化程度较轻。IL-6和IL-21通过激活STAT3促进Th17细胞AREG的表达。STAT3抑制剂可抑制Th17诱导的肠纤维化。AREG通过激活哺乳动物靶标雷帕霉素和MEK，促进人肠肌成纤维细胞的增殖、运动和I型胶原的表达。CD4+T细胞纤维化部位的AREG表达高于非纤维化部位。结论Th17来源的AREG可促进实验性结肠炎和CD患者的肠道纤维化反应。因此，AREG有可能成为治疗CD纤维化的潜在靶点。
Background & AimsIntestinal fibrosis is a significant complication of Crohn’s disease (CD). Gut microbiota reactive Th17 cells are crucial in the pathogenesis of CD; however, how Th17 cells induce intestinal fibrosis is still not completely understood.MethodsIn this study, T-cell transfer model with wild-type (WT) andAreg−/−Th17 cells and dextran sulfate sodium (DSS)-induced chronic colitis model in WT andAreg−/−mice were used. CD4+T-cell expression of AREG was determined by quantitative reverse-transcriptase polymerase chain reaction and enzyme-linked immunosorbent assay. The effect of AREG on proliferation/migration/collagen expression in human intestinal myofibroblasts was determined. AREG expression was assessed in healthy controls and patients with CD with or without intestinal fibrosis.ResultsAlthough Th1 and Th17 cells induced intestinal inflammation at similar levels when transferred intoTcrβxδ−/−mice, Th17 cells induced more severe intestinal fibrosis. Th17 cells expressed higher levels of AREG than Th1 cells. Areg−/−mice developed less severe intestinal fibrosis compared with WT mice on DSS insults. Transfer ofAreg−/−Th17 cells induced less severe fibrosis inTcrβxδ−/−mice compared with WT Th17 cells. Interleukin (IL)6 and IL21 promoted AREG expression in Th17 cells by activating Stat3. Stat3 inhibitor suppressed Th17-induced intestinal fibrosis. AREG promoted human intestinal myofibroblast proliferation, motility, and collagen I expression, which was mediated by activating mammalian target of rapamycin and MEK. AREG expression was increased in intestinal CD4+T cells in fibrotic sites compared with nonfibrotic sites from patients with CD.ConclusionsThese findings reveal that Th17-derived AREG promotes intestinal fibrotic responses in experimental colitis and human patients with CD. Thereby, AREG might serve as a potential therapeutic target for fibrosis in CD.