Table_2_Dynamic atlas of immune cells reveals multiple functional features of macrophages associated with progression of pulmonary fibrosis.csv

Idiopathic pulmonary fibrosis (IPF) is a chronic interstitial lung disease with a high mortality rate and unclarified aetiology. Immune response is elaborately regulated during the progression of IPF, but immune cells subsets are complicated which has not been detailed described during IPF progression. Therefore, in the current study, we sought to investigate the role of immune regulation by elaborately characterize the heterogeneous of immune cells during the progression of IPF. To this end, we performed single-cell profiling of lung immune cells isolated from four stages of bleomycin-induced pulmonary fibrosis—a classical mouse model that mimics human IPF. The results revealed distinct components of immune cells in different phases of pulmonary fibrosis and close communication between macrophages and other immune cells along with pulmonary fibrosis progression. Enriched signals of SPP1, CCL5 and CXCL2 were found between macrophages and other immune cells. The more detailed definition of the subpopulations of macrophages defined alveolar macrophages (AMs) and monocyte-derived macrophages (mo-Macs)—the two major types of primary lung macrophages—exhibited the highest heterogeneity and dynamic changes in expression of profibrotic genes during disease progression. Our analysis suggested that Gpnmb and Trem2 were both upregulated in macrophages and may play important roles in pulmonary fibrosis progression. Additionally, the metabolic status of AMs and mo-Macs varied with disease progression. In line with the published data on human IPF, macrophages in the mouse model shared some features regarding gene expression and metabolic status with that of macrophages in IPF patients. Our study provides new insights into the pathological features of profibrotic macrophages in the lung that will facilitate the identification of new targets for disease intervention and treatment of IPF.

特发性肺纤维化（Idiopathic pulmonary fibrosis, IPF）是一种高死亡率、病因未明的慢性间质性肺疾病。IPF进展过程中免疫应答受到精密调控，但免疫细胞亚群构成复杂，且其在IPF进展中的动态变化尚未得到详尽阐释。因此，本研究旨在通过详尽解析IPF进展过程中免疫细胞的异质性，探究免疫调控在该病中的作用。为此，我们对博莱霉素诱导的肺纤维化——一种模拟人类IPF的经典小鼠模型——四个病程阶段分离的肺部免疫细胞开展了单细胞谱分析。研究结果显示，肺纤维化不同阶段的免疫细胞组成存在显著差异，且随着纤维化进展，巨噬细胞与其他免疫细胞间存在密切的信号互作。研究发现巨噬细胞与其他免疫细胞间存在SPP1、CCL5及CXCL2介导的富集信号通路。对巨噬细胞亚群的进一步细分显示，肺泡巨噬细胞（alveolar macrophages, AMs）与单核细胞源性巨噬细胞（monocyte-derived macrophages, mo-Macs）作为肺部常驻巨噬细胞的两大主要类型，在疾病进展过程中表现出最高的异质性及促纤维化基因表达的动态变化。本研究分析显示，Gpnmb与Trem2在巨噬细胞中均呈上调表达，且可能在肺纤维化进展中发挥重要作用。此外，AMs与mo-Macs的代谢状态随疾病进展发生动态改变。与已发表的人类IPF研究数据一致，该小鼠模型中的巨噬细胞在基因表达及代谢状态方面，与IPF患者体内的巨噬细胞存在部分共通特征。本研究为肺部促纤维化巨噬细胞的病理特征提供了全新见解，将有助于识别IPF疾病干预与治疗的新型靶点。