循环纤维细胞可被受损气道上皮产生的趋化/细胞因子募集至气道并作为哮喘炎症/重塑的效应细胞。本课题组和他人前期研究显示，IL-25（一种Th2型细胞因子）在哮喘患者气道上皮表达上调，且为哮喘气道炎症/重塑的重要调节因子。鉴于此，我们认为，循环纤维细胞很可能表达IL-25受体（IL-17RB/RA），能在IL-25的直接作用下迁移至气道，并分化/活化，产生细胞外基质、促炎/促重塑因子，维持哮喘气道炎症/重塑微环境，从而作为哮喘发病机制中的重要环节。为此，我们拟收集哮喘人群的血液标本，利用已经建立的小鼠慢性哮喘模型组织标本，并建立细胞培养体系，阐述哮喘患者及动物模型循环纤维细胞IL-17RB/RA的表达情况，同时研究IL-25对循环纤维细胞增殖、趋化、分化和活化的影响。本研究可初步明确IL-25-fibrocyte 轴在哮喘炎症和重塑中的潜在作用，为哮喘的进一步治疗提供有益线索。

Circulating fibrocytes can be recruited into the asthmatic bronchi by chemokines/cytokines derived from injured airway epithelium, where they act as the effector cells for airway inflammation and remodeling. We and others showed that IL-25, a pleiotropic T helper type 2(Th2) cytokine, is over-expressed in asthmatic airway epithelium and is a master switch in controlling airway inflammation and remodeling. Thus, we hypothesize that circulating fibrocytes may express the receptors for IL-25, which is the IL-17RB/RA heterodimer. By binding with IL-17RB/RA, IL-25 can promote circulating fibrocytes to migrate into sub-bronchial mucosa layer and augment their differentiation, activation as well as the expressions of extracellular matrix (ECM) and pro-inflammatory/remodeling factors. So IL-25-(IL-17RB/RA+) fibrocyte signal may act as a central role in the pathogenesis of asthma by maintaining an inflammatory and remodeling milieu. To test this, we aim to examine the expressions of IL-17RB/RA on circulating fibrocytes and to explore their correlation with asthma pathogenesis by recruiting subjects with different phenotypes of asthma and by using the tissue samples from alreadily established chronic murine asthma models. We also determine the modulating role of IL-25 on fibrocytes’ phenotypic changes and cellular functions, including cell proliferation, chemotaxis, differentiation and activation, by using in vitro fiborcyte cultures. This study will initially elucidate the core modulatory effect of IL-25-fibrocyte axis on asthma. Also, we can provide some useful clues for the individualized treatment of asthma.

本课题旨在探讨IL-25-Fibrocyte轴在哮喘发病过程中的潜在作用。目前已收集10例正常人及25例哮喘患者的外周血标本，分离得到非贴壁的清除T细胞的外周血单个核细胞，并用流式细胞技术分析Fibrocyte、IL-17RA/RB+Fibrocyte数目在两类人群中的差异。收集哮喘人群肺功能资料，评估IL-17RA/RB+Fibrocyte细胞数目是否与哮喘患者肺功能有相关关系。研究发现，哮喘患者Fibrocyte、IL-17RA/RB+Fibrocyte数目显著高于正常人，且Fibrocyte、IL-17RA/RB+Fibrocyte数目和哮喘患者FEV1/FVC、FEV1%Pred呈显著负相关关系。本研究提示Fibrocyte不仅可以作为哮喘发生发展的生物标志物，而且在哮喘的发病机制中发挥潜在的重要作用，而IL-25通过作用于其细胞表面异源二聚体受体IL-17RA/RB，是Fibrocyte重要的调控因子，故IL-25-（IL-17RA/RB+）Fibrocyte轴可能是调控哮喘的重要分子开关，对此轴的临床干预可能开启哮喘治疗的新途径。