ICAM-1调控髓系抑制性细胞的机制及在哮喘中的病理意义研究

Intercellular cell adhesion molecule-1 (ICAM-1) is closely implicated in asthma and has been viewed as a candidate marker in asthma. However, its immunoregulatory mechanism in asthma remains to be elucidated. Myeloid-derived suppressor cells (MDSC) can inhibit the development of asthma. We recently found: ICAM-1 was highly expressed in MDSC from lungs of mice with asthma; along with the attenuation of asthma in ICAM-1 knockout (KO) mice, the immunosuppressive function of MDSC in ICAM-1 KO mice was significantly enhanced, and the expression of S100A9, an important MDSC regulator, was dramatically up-regulated; deletion of MDSC in ICAM-1 KO mice remarkably aggravated the symptoms of asthma. Thus, we addressed the scientific hypothesis “ICAM-1 promotes the development of asthma through inhibiting lung MDSC expansion via down-regulating the expression of S100A9”. We will carry out our research from the following aspects: investigating the role of ICAM-1 in the regulation of MDSC and its effect on asthma; based on S100A9, clarifying the molecular mechanism of MDSC expansion regulated by ICAM-1; investigating the clinical significance by using clinical samples. Our study will reveal novel molecular mechanism in the regulation of MDSC in asthma, and would provide novel strategy and target for the immunotherapy in asthma.

ICAM-1分子与哮喘的发生发展密切相关，被认为是哮喘的候选标记分子。但ICAM-1参与哮喘发生的机制尚待阐明。髓系抑制性细胞（MDSC）可抑制哮喘的发生。我们前期实验结果表明：哮喘小鼠肺脏来源的MDSC高表达ICAM-1；敲除ICAM-1(ICAM-1 KO)可显著提高肺脏中MDSC的水平及其免疫抑制功能，伴随哮喘症状的缓解，及MDSC调控分子S100A9表达上调；清除ICAM-1 KO小鼠体内MDSC则可加重哮喘症状。据此提出“ICAM-1通过S100A9而抑制肺脏中MDSC的扩增及其免疫抑制功能，进而参与哮喘的发生”。拟从以下方面进行验证：研究ICAM-1对肺脏MDSC的调控作用及对哮喘的影响；以S100A9为主要对象，探讨ICAM-1调控肺脏MDSC的分子机制；利用临床样本研究其临床意义。本项目旨在揭示ICAM-1参与哮喘发生的免疫学机制，为哮喘的免疫治疗提供新策略和新靶标。

ICAM-1分子与哮喘的发生发展密切相关，被认为是哮喘的候选标记分子。但ICAM-1参与哮喘发生的机制尚待阐明。髓系抑制性细胞（MDSC）可抑制哮喘的发生。本项目发现ICAM-1通过S100A9而抑制肺脏中MDSC的扩增及其免疫抑制功能，进而参与哮喘的发生。主要结果如下：哮喘小鼠肺脏来源的MDSC高表达ICAM-1；在OVA诱导的哮喘小鼠模型中，敲除ICAM-1(ICAM-1 KO)可显著提高肺脏中MDSC的水平及其免疫抑制功能，伴随哮喘症状的缓解；清除ICAM-1 KO G-MDSC加重ICAM-1 KO小鼠哮喘症状，而过继转移ICAM-1缺失MDSC明显缓解小鼠肺炎症状；ICAM-1缺失MDSC通过ROS途径抑制T细胞的增殖；ICAM-1缺失主要通过诱导S100A9的表达而促进MDSC的产生。本项目揭示了ICAM-1参与哮喘发生的免疫学机制，为哮喘的免疫治疗提供了新策略。