IL-17A Exacerbates Fibrosis by Promoting the Proinflammatory and Profibrotic Function of Orbital Fibroblasts in TAO
IL-17A Exacerbates Fibrosis by Promoting the Proinflammatory and Profibrotic Function of Orbital Fibroblasts in TAO
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IL-17A 通过促进 TAO 中眼眶成纤维细胞的促炎和促纤维化功能来加剧纤维化
DOI：
10.1210/jc.2016-1882
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发表时间：
2016-08-01
影响因子：
5.8
通讯作者：
Li, Bin
中科院分区：
文献类型：
--
作者：
Fang, Sijie;Huang, Yazhuo;Li, Bin
背景：甲状腺相关性眼病（TAO）的发展与自身免疫功能障碍有关。最近在TAO和Graves病中的发现表明IL-17A也可能参与TAO的自身免疫。目的：探讨产生il - 17a的T细胞在TAO中的致病作用。设计/环境/参与者：从TAO患者和健康受试者中采集血液样本和眼眶成纤维细胞（OFs）。主要观察指标：流式细胞术、实时PCR、细胞因子特异性ELISA、Western blotting。结果：我们发现TAO患者中il - 17a生成T细胞的比例明显增加，TAO眼眶中CD4（+）和CD8(+) T细胞的募集也明显增加。TAO眼眶组织表达IL-17A受体、IL-17A及其相关细胞因子较多，纤维化改变较正常对照严重。此外，我们证实IL-17A可以增强OFs的促炎功能，并刺激OFs而不是眼睑成纤维细胞的细胞外基质蛋白的产生。这种增强的机制主要依赖于mapk的激活。最后，我们观察到去泛素酶抑制剂vialinin A可以下调TAO患者视黄酸受体相关孤儿受体γ t的表达，降低IL-17A水平。结论：我们的观察结果说明了il - 17a产生的T细胞在TAO的炎症反应和纤维化中的潜在致病作用。养鸡素A对维甲酸受体相关孤儿受体γ - t水平降低的影响暗示其在未来可能作为一种新的治疗TAO和其他自身免疫性疾病的药物。
Context: The development of thyroid-associated ophthalmopathy (TAO) is associated with self-immune dysfunction. Recent findings in TAO and Graves' disease indicate that IL-17A may also be involved in the autoimmunity of TAO.Objective: We sought to investigate the pathogenic function of IL-17A-producing T cells in TAO.Design/Setting/Participants: Blood samples and orbital fibroblasts (OFs) were collected from TAO patients and healthy subjects.Main Outcome Measures: Flow cytometry, real-time PCR, cytokine-specific ELISA, and Western blotting were performed.Results: Here, we showed a significantly higher proportion of IL-17A-producing T cells in TAO patients and the recruitment of both CD4(+) and CD8(+) T cells in TAO orbits. TAO orbital tissues expressed more IL-17A receptor, IL-17A, and its related cytokines, with severe fibrotic change compared with normal controls. Furthermore, we validated that IL-17A could enhance the proinflammatory function of OFs and stimulate the production of extracellular matrix proteins in OFs but not eyelid fibroblasts. The mechanisms involved in this enhancement mainly relied onMAPKactivation. Finally, weobserved that the deubiquitinase inhibitor vialinin A could down-regulate retinoic acid receptor-related orphan receptor-gamma t expression and decrease IL-17A level in TAO patients.Conclusion: Our observations illustrate the potential pathogenic role of IL-17A-producing T cells in the inflammatory response and fibrosis of TAO. The effect of vialinin A on the reduction of retinoic acid receptor-related orphan receptor-gamma t level implicates its potential role as a novel therapeutic agent for TAO and other autoimmune disorders in the future.