Aryl hydrocarbon receptor signals attenuate lung fibrosis in the bleomycin-induced mouse model for pulmonary fibrosis through increase of regulatory T cells
Aryl hydrocarbon receptor signals attenuate lung fibrosis in the bleomycin-induced mouse model for pulmonary fibrosis through increase of regulatory T cells
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DOI：
10.1186/s13075-020-2112-7
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发表时间：
2020-02-07
影响因子：
4.9
通讯作者：
Takeuchi, Tsutomu
中科院分区：
文献类型：
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作者：
Takei, Hiroshi;Yasuoka, Hidekata;Takeuchi, Tsutomu
背景间质性肺疾病（ILD）是结缔组织疾病（CTDs）的严重并发症。尽管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尚不清楚。最近的报道表明，各种配体（如色氨酸衍生物）激活芳烃受体（AhR）信号可诱导超免疫反应，并参与自身免疫。我们利用博来霉素（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。方法经气管给药于C57BL/6JJcl小鼠，并在给药后的第0、1、2天分别腹腔注射天然AhR配体5,11-二氢吲哚[3,2-b]咔唑-6-甲醛（FICZ）或对照物。第3周处死小鼠，用Ashcroft评分法测定肺纤维化组织学变化，用Sircol法测定肺内可溶性胶原沉积水平。流式细胞术分析肺内浸润免疫细胞的数量。结果ficz治疗组小鼠Ashcroft评分和可溶性胶原蛋白水平均明显低于对照组。此外，在治疗后3周内，ficz处理小鼠的存活率显著高于对照组。有趣的是，流式细胞术分析显示，FICZ处理小鼠肺中CD4(+)Foxp3（+）调节性T细胞（Tregs）数量显著增加，CD4(+)IFN γ(+)和γ δ +IL-17A(+) T细胞数量减少，而T、B和NK细胞总数未受FICZ处理影响。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treg和抑制炎症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病相关ILD的有效治疗靶点。
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(+)IFN gamma(+) and gamma delta+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.