激素敏感性降低是重症（难治性）哮喘的临床特征，其发生与Th1细胞过度募集有关。Th1募集依赖CXCL10-CXCR3轴的趋化作用，CXCL10受IFN-γ及IRF1正向调控。我们发现GLCCI1降低导致哮喘个体激素敏感性减弱，GLCCI1敲除使哮喘小鼠肺组织IRF1及IFN-γ表达进一步增高。据此推测GLCCI1下调弱化激素对IRF1的抑制作用，后者使支气管上皮细胞中CXCL10上调，CXCL10与Th1细胞表达的CXCR3结合进而募集Th1至气道周围。本项目拟探讨：①哮喘患者激素敏感性存在差异的状态下，GLCCI1与Th1募集的对应关系；②将支气管上皮细胞与CD4+T细胞共培养，明确哮喘所致GLCCI1下调可否促进IRF1表达进而通过CXCL10-CXCR3轴过度募集Th1；③建立GLCCI1敲除小鼠哮喘模型，验证GLCCI1下调可否经上述机制过度募集Th1从而降低激素敏感性。

Glucocorticoid insensitivity viewed as a clinical feature for severe asthma is associated with excessive Th1 cells recruitments. Th1 cells recruitments are relied on the chemotaxis of CXCL10-CXCR3 axis, and CXCL10 is positively regulated by IFN-γ and IRF1. We previously found that GLCCI1 deficiency not only increased the expression of interferon-γ (IFN-γ) and interferon regulatory factor 1 (IRF1) in asthma mouse model, but also related to glucocorticoid insensitivity in asthma patients. Therefore, it is speculated that lower expression of GLCCI1 could reduce the glucocorticoid restriction on IRF1, meanwhile higher expression of IRF1 further recruits Th1 cells to airway to produce type 1 inflammation through making CXCL10 combining with CXCR3 in the Th1 cells. Accordingly, this project intends to carry out the following works: ① To explore the relationship between Th1 cells recruitments induced by GLCCI1 deficiency and glucocorticoid insensitivity in asthma patients. ② To investigate whether or not GLCCI1 deficiency could facilitate IRF1 expression which leads to excessive Th1 cells recruitments via CXCL10-CXCR3 axis by co-culture bronchial epithelial cells with CD4+T cells. ③ The GLCCI1 deficiency mice will be used to build asthmatic model, and the aim is to research GLCCI1 deficiency whether or not generates excessive Th1 cells recruitments and further results in glucocorticoid insensitivity through mechanism described above.