Division of Rheumatology, Department of Internal Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, Japan.
Division of Rheumatology, Department of Internal Medicine, Fujita Health University School of Medicine, 1-98 Dengakugakubo, Kutsukake-cho, Aichi, Japan.
Arthritis Res Ther. 2020 Feb 7;22(1):20. doi: 10.1186/s13075-020-2112-7.
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.
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.
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 CD4Foxp3 regulatory T cells (Tregs) was significantly increased and CD4IFNγ and γδIL-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.
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.
间质性肺病（ILD）是结缔组织疾病（CTD）的严重并发症。虽然遗传和环境因素引发的免疫失调被认为会引发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（如色氨酸衍生物）激活芳香烃受体（AhR）信号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研究了 AhR 信号对肺纤维化过程和免疫特征变化的影响。
BLM 通过气管内给药给予 C57BL/6JJcl 小鼠，随后在 BLM 给药后第 0、1 和 2 天分别通过腹腔内注射 5,11-二氢吲哚并[3,2-b]咔唑-6-羧醛（FICZ），一种天然 AhR 配体或载体。在第 3 周处死小鼠，通过 Ashcroft 评分量化肺组织学变化，通过 Sircol 测定法测定肺中可溶性胶原蛋白水平来量化肺纤维化。使用流式细胞术分析浸润到肺部的免疫细胞群体。
与载体组相比，FICZ 处理小鼠的 Ashcroft 评分和可溶性胶原蛋白水平均显著降低。此外，在治疗后 3 周内，FICZ 处理小鼠的存活率明显高于对照组。有趣的是，流式细胞术分析显示，FICZ 处理小鼠肺中 CD4Foxp3 调节性 T 细胞（Tregs）的数量显著增加，CD4IFNγ和γδIL-17A T 细胞减少，而 T、B 和 NK 细胞的总数不受 FICZ 处理的影响。
我们的研究结果表明，在 BLM 诱导的纤维化模型中，刺激 AhR 信号通过增加 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 的有用治疗靶点。
