Yu Xiu, Li Lifei, Cai Bicheng, Zhang Wei, Liu Quan, Li Nan, Shi Xing, Yu Li, Chen Rongchang, Qiu Chen
Key Laboratory of Shenzhen Respiratory Diseases, Institute of Shenzhen Respiratory Diseases, Department of Respiratory and Critical Care Medicine, Shenzhen People's Hospital (The First Affiliated Hospital, Southern University of Science and Technology; The Second Clinical Medical College, Jinan University), Shenzhen, 518020, China.
Department of Infectious Diseases, The First Affiliated Hospital (Shenzhen People's Hospital), School of Medicine, Southern University of Science and Technology, Shenzhen, 518020, China.
Respir Res. 2024 Feb 5;25(1):76. doi: 10.1186/s12931-024-02706-4.
Asthma is a heterogeneous disease characterized by airway inflammation and remodeling, whose pathogenetic complexity was associated with abnormal responses of various cell types in the lung. The specific interactions between immune and stromal cells, crucial for asthma pathogenesis, remain unclear. This study aims to determine the key cell types and their pathological mechanisms in asthma through single-cell RNA sequencing (scRNA-seq).
A 16-week mouse model of house dust mite (HDM) induced asthma (n = 3) and controls (n = 3) were profiled with scRNA-seq. The cellular composition and gene expression profiles were assessed by bioinformatic analyses, including cell enrichment analysis, trajectory analysis, and Gene Set Enrichment Analysis. Cell-cell communication analysis was employed to investigate the ligand-receptor interactions.
The asthma model results in airway inflammation coupled with airway remodeling and hyperresponsiveness. Single-cell analysis revealed notable changes in cell compositions and heterogeneities associated with airway inflammation and remodeling. GdT17 cells were identified to be a primary cellular source of IL-17, related to inflammatory exacerbation, while a subpopulation of alveolar macrophages exhibited numerous significantly up-regulated genes involved in multiple pathways related to neutrophil activities in asthma. A distinct fibroblast subpopulation, marked by elevated expression levels of numerous contractile genes and their regulators, was observed in increased airway smooth muscle layer by immunofluorescence analysis. Asthmatic stromal-immune cell communication significantly strengthened, particularly involving GdT17 cells, and macrophages interacting with fibroblasts. CXCL12/CXCR4 signaling was remarkedly up-regulated in asthma, predominantly bridging the interaction between fibroblasts and immune cell populations. Fibroblasts and macrophages could jointly interact with various immune cell subpopulations via the CCL8/CCR2 signaling. In particular, fibroblast-macrophage cell circuits played a crucial role in the development of airway inflammation and remodeling through IL1B paracrine signaling.
Our study established a mouse model of asthma that recapitulated key pathological features of asthma. ScRNA-seq analysis revealed the cellular landscape, highlighting key pathological cell populations associated with asthma pathogenesis. Cell-cell communication analysis identified the crucial ligand-receptor interactions contributing to airway inflammation and remodeling. Our findings emphasized the significance of cell-cell communication in bridging the possible causality between airway inflammation and remodeling, providing valuable hints for therapeutic strategies for asthma.
哮喘是一种异质性疾病，其特征为气道炎症和重塑，其发病机制的复杂性与肺内各种细胞类型的异常反应有关。免疫细胞与基质细胞之间的特定相互作用对哮喘发病机制至关重要，但仍不清楚。本研究旨在通过单细胞RNA测序（scRNA-seq）确定哮喘中的关键细胞类型及其病理机制。
用scRNA-seq对屋尘螨（HDM）诱导的哮喘小鼠模型（n = 3）和对照组（n = 3）进行16周的分析。通过生物信息学分析评估细胞组成和基因表达谱，包括细胞富集分析、轨迹分析和基因集富集分析。采用细胞间通讯分析来研究配体-受体相互作用。
哮喘模型导致气道炎症，伴有气道重塑和高反应性。单细胞分析揭示了与气道炎症和重塑相关的细胞组成和异质性的显著变化。γδT17细胞被确定为IL-17的主要细胞来源，与炎症加重有关，而肺泡巨噬细胞亚群表现出许多与哮喘中性粒细胞活动相关的多种途径中显著上调的基因。通过免疫荧光分析，在气道平滑肌层增厚处观察到一个独特的成纤维细胞亚群，其特征是许多收缩基因及其调节因子的表达水平升高。哮喘基质-免疫细胞通讯显著增强，特别是涉及γδT17细胞以及巨噬细胞与成纤维细胞的相互作用。CXCL12/CXCR4信号在哮喘中显著上调，主要介导成纤维细胞与免疫细胞群体之间的相互作用。成纤维细胞和巨噬细胞可通过CCL8/CCR2信号共同与各种免疫细胞亚群相互作用。特别是，成纤维细胞-巨噬细胞细胞回路通过IL1B旁分泌信号在气道炎症和重塑的发展中起关键作用。
我们的研究建立了一个重现哮喘关键病理特征的小鼠模型。scRNA-seq分析揭示了细胞图谱，突出了与哮喘发病机制相关的关键病理细胞群体。细胞间通讯分析确定了导致气道炎症和重塑的关键配体-受体相互作用。我们的研究结果强调了细胞间通讯在连接气道炎症和重塑之间可能的因果关系中的重要性，为哮喘治疗策略提供了有价值的线索。
