嗜酸性粒细胞调控肺局部免疫反应的作用和分子机制研究

Eosinophils have long been recognized as terminal effector cells in pulmonary immune response, and their functions in regulating allergic diseases (i.e. asthma) and parasite infection are well documented. Recent accumulating evidence has suggested that eosinophils could in turn regulate Th2 immune response, but the molecular mechanisms were not fully understood. Our preliminary data suggested that eosinophils not only regulated the asthmatic inflammatory response, but also played crucial roles in classical EOS-irrelated disease models such as LPS- or cigarette smoking- induced pulmonary inflammation, and that their effects and mechanisms might be completely different. We have also noticed that EOS-produced CCL6 might play a pivotal role during these processes. Therefore, this project aims at exploring the regulatory roles and underlying molecular mechanisms of eosinophils and CCL6 in pulmonary immunity. By using eosinophil- and CCL6-related transgenic and knockout mice to establish the innate immunity- and adaptive immunity-dominant pulmonary disease models, and following with analysis of the inflammation infiltration, immune cells, and protemic or genetic analysis in each murine model, this project will expect to discover new regulating functions of eosinophils in pulmonary immune response, and will clarify the molecular mechanisms, thereby demonstrating new insights and theoretical foundation for pulmonary immune regulation, and providing novel therapeutic strategies for eosinophil-related pulmonary disorders.

嗜酸性粒细胞（EOS）过去被认为仅仅是肺局部免疫反应中的效应细胞，在哮喘等过敏性疾病和寄生虫感染中具有重要作用。然而近期有证据提示EOS具有调节Th2型免疫反应的功能，但分子机制所知甚少。我们的前期研究表明：EOS不仅能介导哮喘炎症反应，在传统的非EOS相关的疾病模型如LPS或香烟烟雾诱导的肺部炎症中也能起到关键调控作用，而且其效果和机制可能完全不同；进一步研究发现EOS分泌的CCL6可能在EOS的调控过程中起到关键作用。因此，本项目拟探究EOS调控肺局部免疫反应的作用和分子机制。我们将利用EOS及CCL6相关的各种转基因小鼠，分别建立以固有免疫和适应性免疫为主的肺部疾病模型，通过检测肺部炎症与免疫细胞改变以及组学分析等，以阐明EOS以及CCL6在肺局部免疫反应中的新型调控作用及分子机制，预期为肺局部免疫调控机制提供新的发现和理论依据，同时为相关疾病的防治提供新的防治靶点。

嗜酸性粒细胞（Eos）过去被认为仅仅是肺局部免疫反应中的效应细胞，在哮喘等过敏性疾病和寄生虫感染中具有重要作用。近期研究还发现，Eos也具有调节Th2型免疫反应及其他生命进程等功能，但分子机制所知甚少。本项目利用Eos相关基因修饰小鼠和肺局部免疫相关动物疾病模型，通过体内外实验，主要探究以下四方面内容：①Eos在急性肺损伤模型中的调控作用；②Eos在COPD模型中的调控作用；③Eos来源的CCL6在肺固有免疫中的调控作用；④Eos来源的CCL6对于哮喘炎症的调控作用。.主要得出以下研究结果：①LPS急性肺损伤早期肺部存在CD101- Eos增多，该种Eos可以通过合成Protectin D1抑制中性粒细胞炎症。②香烟烟雾暴露联合弹性蛋白酶诱导的COPD模型小鼠肺部早期即存在Eos聚集，这部分Eos可以促进pre-DC向肺组织迁移并促进CD11b+ DC的发育、活化，进而促进Th17型免疫反应及中性粒细胞肺部炎症。③哮喘环境中Eos表达CCL6增高，并通过CCL6-CCR1信号进一步促进Eos的分化从而促进哮喘炎症的发生与进展。.本项目的研究结果达到了课题的预期研究目标，即阐明了Eos以及CCL6在肺局部免疫反应中的新型调控作用及分子机制，为肺局部免疫调控机制提供新的理论依据，同时为急性肺损伤、COPD和哮喘等疾病的的防治提供新的治疗靶点。