(IL-25/IL-33/TSLP)-Fibrocyte 轴在过敏性气道疾病中的致病作用及机制研究

Allergic airway diseases are a group of heterogeneous diseases mediated by T helper type 2(Th2) immune response and characterized with airway inflammation and remodeling, includiing allergic asthma, allergic rhinitis and chronic sinusitis. Recently, abnormal epithelial-mesenchymal crosstalk is considered to be the core pathogenesis of allergic airway disease, however, the key regulatory factors and molecular events involved still remain unclear. Epithelium-derived cytokines, including IL-25, IL-33 and TSLP, are shown to promote the Th2 immune response. Also, circulating fibrocyte is an important mesenchymal cell that can mediate tissue remodeling. We previously found that IL-25 - circulating fibrocyte axis was significantly up-regulated in patients with asthma, which greatly contributed to asthmatic airway inflammation and remodeling. Considering the redundancy of cytokines and 'one united airway' theory, we hypothesize that IL-25/IL-33/TSLP-fibrocyte axis may play a vital role in the abnormal epithelial-mesenchymal crosstalk in allergic airway diseases. On the basis of previous work, we aim to further explore whether the IL-25 /IL-33/TSLP-circulating fibrocytel axis is a common key molecular event in allergic airway disease by using the biological sample of patients with asthma, rhinitis, sinusitis with/without nasal polyps, by establishing asthma and rhinitis/sinusitis mice model, and by building the cell culture/co-culture system. This will provide potential targets for the common treatment of patients with allergic airway diseases.

过敏性气道疾病（AADs）是一类以Th2型免疫反应介导的慢性气道炎症和异常修复疾病，包括过敏性哮喘、过敏性鼻炎和慢性鼻窦炎。目前认为上皮-间质异常通讯是过敏性气道疾病的核心发病机制，但参与其中的关键分子事件尚未明确。IL-25/IL-33/TSLP是上皮来源的促Th2型免疫反应的细胞因子，而循环纤维细胞是一种可介导组织重塑的重要间质细胞，我们前期研究发现IL-25-循环纤维细胞轴在哮喘患者中表达明显上调，且和哮喘严重程度、损伤修复相关。鉴于细胞因子生物学作用的冗余性和“同一气道“理论，我们认为IL-25/IL-33/TSLP-纤维细胞轴可能参与过敏性气道疾病上皮-间质异常通讯。为此，我们拟利用AADs患者生物标本库，制作相应小鼠模型，构建细胞培养/共培养体系，明确IL-25/IL-33/TSLP-循环纤维细胞轴是否是调控AADs的共有关键分子事件，从而为该类疾病患者的共同治疗提供潜在靶点。

过敏性气道疾病（allergic airway diseases, AADs）是指一组以Th2型细胞因子（T-helper type 2 cytokines）反应为主要免疫病理学特征，以气道黏膜慢性炎症和异常重塑为基本组织病理学特征的异质性疾病群，包括过敏性鼻炎（allergic rhinitis, AR）、过敏性哮喘（allergic asthma, AA）和慢性鼻窦炎（chronic rhinosinusitis, CRS）。参与AADs发生发展的共同的调控因子和事件鲜有报道。本课题旨在探讨IL-25/IL-33/TSLP（上皮源性Th2型细胞因子）-fibrocytes（纤维细胞）轴在AADs气道黏膜炎性损伤及异常修复中的潜在作用。本课题研究发现：（1）AA、AR、CRS患者外周血IL-25R+/IL-33R+/TSLPR+-fibrocytes细胞数目显著高于正常人群；（2）OVA诱导的AA小鼠模型气道组织标本中IL-25R+/IL-33R+/TSLPR+-fibrocytes细胞数目显著高于生理盐水对照小鼠；（3）体外细胞培养研究发现，IL-25可以促进fibrocytes细胞募集并发生促纤维化表型转化，表现为增强的迁移能力；I型胶原（collagen I）、III型胶原（Collagen III）、纤维连接蛋白（fibronecin）、结缔组织生长因子（connective tissue growth factor, CTGF）表达显著上调；IL-25可介导气道上皮细胞-fibrocytes间的异常通讯。该研究提示，IL-25/IL-33/TSLP可能通过介导fibrocytes募集和表型转化而参与AADs的气道炎症和重塑的发生发展。故而，针对于IL-25/IL-33/TSLP-fibrocytes轴的靶向治疗可能是治疗AADs的新途径。