BACKGROUND Interstitial lung disease (ILD) is a serious complication of connective tissue diseases (CTDs). Although immune dysregulation triggered by genetic and environmental factors is thought to provoke inflammation and subsequent fibrosis, precise mechanisms of these processes remain unclear. Recent reports suggest that activation of aryl hydrocarbon receptor (AhR) signals by various ligands such as tryptophan derivatives can induce hyper-immune responses and are involved in autoimmunity. We investigated the effects of AhR signals on the process of lung fibrosis and changes in immunological features using a bleomycin (BLM)-induced lung fibrosis mouse model. METHODS BLM was administered intratracheally to C57BL/6JJcl mice and either 5,11-dihydroindolo[3,2-b]carbazole-6-carboxaldehyde (FICZ), a natural AhR ligand, or vehicle was subsequently injected intraperitoneally on day 0, 1, and 2 from BLM administration. Mice were sacrificed at week 3, and lung fibrosis was quantified by the histological changes using the Ashcroft score and deposition of soluble collagen levels in the lung using Sircol assay. The population of immune cells infiltrated into the lungs was analyzed using flow cytometry. RESULTS Both the Ashcroft score and soluble collagen level in FICZ-treated mice were significantly lower than those in the vehicle group. Moreover, the survival rate of FICZ-treated mice was significantly higher than that of control mice during the 3 weeks after treatment. Interestingly, flow cytometric analysis revealed that the number of CD4+Foxp3+ regulatory T cells (Tregs) was significantly increased and CD4+IFNγ+ and γδ+IL-17A+ T cells were decreased in the lungs of FICZ-treated mice, while the total number of T, B, and NK cells were unaffected by FICZ treatment. CONCLUSIONS Our findings suggest that stimulation of AhR signals attenuated lung fibrosis by increasing Tregs and suppressing inflammatory T cell subsets in a BLM-induced fibrosis model. AhR signaling pathways may therefore be useful therapeutic targets for connective tissue disease-associated ILD.

中文翻译：

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芳烃受体信号通过增加调节性T细胞来减轻博来霉素诱导的小鼠肺纤维化模型中的肺纤维化。

背景技术间质性肺疾病（ILD）是结缔组织疾病（CTD）的严重并发症。尽管认为由遗传和环境因素触发的免疫失调会引起炎症和随后的纤维化，但这些过程的确切机制仍不清楚。最近的报告表明，各种配体（例如色氨酸衍生物）对芳烃受体（AhR）信号的激活可以诱导超免疫反应，并参与自身免疫。我们使用博来霉素（BLM）诱导的肺纤维化小鼠模型调查了AhR信号对肺纤维化过程和免疫学特征变化的影响。方法向C57BL / 6JJcl小鼠气管内施用BLM和天然AhR配体5,11-二氢吲哚并[3,2-b]咔唑-6-甲醛（FICZ），或随后在BLM给药的第0、1和2天腹膜内注射媒介物。在第3周处死小鼠，并使用Ashcroft评分通过组织学变化定量肺纤维化，并使用Sircol测定法定量肺中可溶性胶原水平的沉积。使用流式细胞仪分析了渗入肺的免疫细胞的数量。结果FICZ处理的小鼠的Ashcroft评分和可溶性胶原水平均显着低于载体组。此外，在治疗后3周内，用FICZ治疗的小鼠的存活率显着高于对照小鼠。有趣的是 流式细胞仪分析显示，FICZ处理的小鼠肺中CD4 + Foxp3 +调节性T细胞（Tregs）的数目显着增加，而CD4 +IFNγ+和γδ+ IL-17A + T细胞的数目减少，而T总数，B和NK细胞不受FICZ处理的影响。结论我们的发现表明，在BLM诱导的纤维化模型中，AhR信号的刺激通过增加Tregs和抑制炎症性T细胞亚群来减轻肺纤维化。因此，AhR信号通路可能是结缔组织疾病相关ILD的有用治疗靶标。结论我们的发现表明，在BLM诱导的纤维化模型中，AhR信号的刺激通过增加Treg和抑制炎性T细胞亚群而减轻了肺纤维化。因此，AhR信号通路可能是结缔组织疾病相关ILD的有用治疗靶标。结论我们的发现表明，在BLM诱导的纤维化模型中，AhR信号的刺激通过增加Tregs和抑制炎症性T细胞亚群来减轻肺纤维化。因此，AhR信号通路可能是结缔组织疾病相关ILD的有用治疗靶标。