地塞米松通过调节 TGF-β/Smad3 信号促进 Th17/Treg 细胞恢复平衡来缓解肺肉样瘤病

IF 3.7 4区 医学 Q2 CELL BIOLOGY Cellular immunology Pub Date : 2024-01-01 DOI:10.1016/j.cellimm.2023.104781
Yu Zhang , Xuan Jiang , Qing Wang , Jiayi Wu , Juan Zhou
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引用次数: 0

摘要

肺肉样病是一种与 Th17/Treg 细胞失衡密切相关的免疫介导疾病。地塞米松已被证明可以调节肉样红细胞增多症患者的炎症和免疫反应。然而,地塞米松调节肉样瘤病中Th17/Treg细胞平衡的潜在机制仍不明确。在此,我们阐明了TGF-β/Smad3信号在肺肉样瘤病发展中的功能作用,并探讨了地塞米松治疗肺肉样瘤病的内在机制。我们发现肺肉样病患者的 TGF-β/Smad3 通路失活。为了研究 TGF-β/Smad3 信号传导在体内的功能,我们制作了痤疮丙酸杆菌(PA)诱导的小鼠模型。数据表明,用中和抗体抑制 IL17A 和用 SRI-011381 激活 TGF-β/Smad3 信号可减轻肉芽肿小鼠模型中肉芽肿的形成。此外,我们还发现,PA 处理后,小鼠支气管肺泡灌洗液(BALF)和外周血中的 Th17/Treg 细胞比率增加。Th17细胞产生的细胞因子(IL-17A、IL-23)在PA治疗小鼠的BALF中浓度上调,而Treg细胞产生的细胞因子(IL-10、TGF-β1)则显著下降。事实证明,IL-17A 中和抗体或 SRI-011381 可挽救 PA 诱导的 IL-17A、IL-23、IL-10 和 TGF-β1 的浓度变化。此外,我们还证实地塞米松治疗激活了肺肉样瘤病小鼠肺组织中的 TGF-β/Smad3 信号传导。地塞米松还促进了Th17/Treg比例的重新平衡,并减轻了肺肉样瘤病中肉芽肿的形成。总之,地塞米松能激活TGF-β/Smad3信号传导,诱导Th17/Treg重新平衡,缓解肺肉样瘤病,这表明地塞米松具有治疗肺肉样瘤病的潜力。
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Dexamethasone alleviates pulmonary sarcoidosis by regulating the TGF-β/Smad3 signaling to promote Th17/Treg cell rebalance

Pulmonary sarcoidosis is an immune-mediated disorder closely related to Th17/Treg cell imbalance. Dexamethasone has been shown to regulate inflammation and immune responses in sarcoidosis patients. However, the underlying mechanisms of dexamethasone regulating Th17/Treg balance in sarcoidosis remain elusive. Herein, we elucidated the function role of TGF-β/Smad3 signaling in pulmonary sarcoidosis development and explored the underlying mechanism of dexamethasone in treating pulmonary sarcoidosis. We found that the TGF-β/Smad3 pathway was inactivated in pulmonary sarcoidosis patients. Propionibacterium acnes (PA) induced mouse model was generated to investigate the function of TGF-β/Smad3 signaling in vivo. Data indicated that IL17A inhibition with neutralizing antibody and activation of TGF-β/Smad3 signaling with SRI-011381 alleviated granuloma formation in the sarcoidosis mouse model. Moreover, we revealed that the Th17/Treg cell ratio was increased with PA treatment in mouse bronchoalveolar lavage fluid (BALF) and peripheral blood. The concentration of cytokines produced by Th17 cells (IL-17A, IL-23) was up-regulated in the BALF of PA-treated mice, while those produced by Tregs (IL-10, TGF-β1) presented significant reduction. The treatment of IL-17A neutralizing antibody or SRI-011381 was demonstrated to rescue the PA-induced changes in the concentration of IL-17A, IL-23, IL-10, and TGF-β1. Additionally, we demonstrated that dexamethasone treatment activated the TGF-β/Smad3 signaling in the lung tissues of pulmonary sarcoidosis mice. Dexamethasone was also revealed to promote the rebalancing of the Th17/Treg ratio and attenuated the granuloma formation in pulmonary sarcoidosis. In conclusion, dexamethasone activates the TGF-β/Smad3 signaling and induces Th17/Treg rebalance, alleviating pulmonary sarcoidosis, which suggests the potential of dexamethasone in treating pulmonary sarcoidosis.

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来源期刊
Cellular immunology
Cellular immunology 生物-免疫学
CiteScore
8.20
自引率
2.30%
发文量
102
审稿时长
30 days
期刊介绍: Cellular Immunology publishes original investigations concerned with the immunological activities of cells in experimental or clinical situations. The scope of the journal encompasses the broad area of in vitro and in vivo studies of cellular immune responses. Purely clinical descriptive studies are not considered. Research Areas include: • Antigen receptor sites • Autoimmunity • Delayed-type hypersensitivity or cellular immunity • Immunologic deficiency states and their reconstitution • Immunologic surveillance and tumor immunity • Immunomodulation • Immunotherapy • Lymphokines and cytokines • Nonantibody immunity • Parasite immunology • Resistance to intracellular microbial and viral infection • Thymus and lymphocyte immunobiology • Transplantation immunology • Tumor immunity.
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