Single-cell analysis reveals alterations in cellular composition and cell-cell communication associated with airway inflammation and remodeling in asthma

Yu，Xiu1; Li，Lifei1; Cai，Bicheng1; Zhang，Wei2; Liu，Quan3; Li，Nan1; Shi，Xing1; Yu，Li4; Chen，Rongchang1; Qiu，Chen1

2024-12-01

10.1186/s12931-024-02706-4

Respiratory Research   影响因子和分区

1465-9921

1465-993X

Background: 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). Methods: 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. Results: 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. Conclusions: 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.

Airway inflammation Airway remodeling Asthma Cell-cell communication Single-cell RNA-sequencing

SCI

英语

第一 ; 通讯

CLINICAL MEDICINE

2-s2.0-85184451381

Scopus

1.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
2.Department of Infectious Diseases,The First Affiliated Hospital (Shenzhen People’s Hospital),School of Medicine,Southern University of Science and Technology,Shenzhen,518020,China
3.Department of Biochemistry,Key University Laboratory of Metabolism and Health of Guangdong,School of Medicine,Southern University of Science and Technology,Shenzhen,518055,China
4.Longgang Central Hospital of Shenzhen,Shenzhen,LongGang District,518116,China

Yu，Xiu,Li，Lifei,Cai，Bicheng,et al. Single-cell analysis reveals alterations in cellular composition and cell-cell communication associated with airway inflammation and remodeling in asthma[J]. Respiratory Research,2024,25(1).

Yu，Xiu.,Li，Lifei.,Cai，Bicheng.,Zhang，Wei.,Liu，Quan.,...&Qiu，Chen.(2024).Single-cell analysis reveals alterations in cellular composition and cell-cell communication associated with airway inflammation and remodeling in asthma.Respiratory Research,25(1).

Yu，Xiu,et al."Single-cell analysis reveals alterations in cellular composition and cell-cell communication associated with airway inflammation and remodeling in asthma".Respiratory Research 25.1(2024).