肺脏巨噬细胞和树突状细胞发育分化及功能的表观遗传调控机制

Lung-resident macrophages and dendritic cells (DC) are critical for innate immune defense and controlling organ homeostasis. The lung is continuously exposed to variety of inhaled solid and liquid particles including pathogens and thus maintains a special tissue microenvironment. Due to the unique lung microenvironment, the development, differentiation and function of resident macrophages and DCs are quite different from that of macrophages and DCs in other tissues. However, the molecular mechanisms of regulation of development, differentiation and functions of resident macrophages and DCs still remain largely unclear. Here for the first time we found that histone deacetylase (HDAC) 1 and 2 are required for alevolar macrophages (AM) development. Deficiency of Hdac1/2 leads to impaired development of AM as well as decreased number of DC, indicating a novel mechanism of histone modification in orchestrating development of lung-resident AM and DC. In this study, we propose to investigate the molecular networks by which HDAC1/2 specifically determines identity and plasticity of AM and DC under lung microenvironment and the in vivo significance of effects of HDAC1/2 in lung infectious diseases. The proposed study will contribute to our understanding of histone deacetylases in regulation of AM and DC differentiation and function and shed light on designing novel therapeutic approaches in lung diseases through targeting histone modification.

肺脏巨噬细胞(alevolar macrophage, AM)和树突状细胞(dendritic cell, DC)在维持器官稳态和免疫防御中至关重要 。由于处于特殊的组织微环境,肺部免疫细胞的发育分化具有特殊性,然而其发育分化调控的分子机制尚不清楚。我们首次发现组蛋白去乙酰化酶HDAC1/2对于肺部AM和DC的发育分化是必须的,HDAC1/2缺失导致肺部AM发育在早期停滞及肺部DC数目显著减少,提示组蛋白乙酰化修饰对肺部AM和DC发育分化调节的全新作用。本项目将围绕组蛋白乙酰化对肺部AM和DC发育分化及功能调控的关键科学问题,鉴定HDAC1/2调控肺部AM和DC发育分化及功能相关的关键分子, 解析其调控的分子机制。预期该项目将在阐明肺部AM和DC 发育分化及功能的表观遗传调控机制和肺免疫稳态形成和维持机制等方面获得具有创新性的的成果,为肺部感染疾病的治疗和药物研发提供重要理论基础。

肺脏是呼吸系统最主要的器官，承载着气体交换，免疫调节，血小板生成等多种重要功能。外界可吸入颗粒物如病原微生物、尘埃以及有害气体会随空气进入呼吸道，严重时可引起呼吸系统感染及炎性疾病。肺脏巨噬细胞（Alevolar macrophage, AM）和树突状细胞（Dendritic cell, DC）在维持肺部微环境稳态和免疫防御中至关重要。因此，深入了解AM和DC相关的免疫调控机制对于呼吸系统疾病防治具有深远意义。由于特殊的组织微环境，肺部免疫细胞的发育分化具有特殊性，然而其发育分化调控的分子机制尚不清楚。本项目研究首次发现组蛋白去乙酰化酶对于维持肺部AM和DC的稳态是必须的。我们通过条件性基因敲除小鼠，发现Hdac1/2缺失导致肺部AM发育在早期停滞及肺部DC数目显著减少，而不影响其他组织定居巨噬细胞。在分子机制上，Hdac1/2的缺失导致促凋亡基因的表达升高，引发AM的细胞凋亡。另外，我们发现Hdac1/2缺陷小鼠肺泡出现蛋白过度沉积且不能正常抵御流感病毒的感染。通过回补骨髓来源的巨噬细胞能够成功缓解Hdac1/2缺陷小鼠的肺泡蛋白沉积症状，同时能够恢复其抗流感病毒能力。本项目成果阐明组蛋白乙酰化修饰对肺部AM和DC发育分化的关键调节作用，拓展对肺部疾病相关免疫调控的认知，并为相关临床实践和药物研发提供重要理论基础。