The influence of CLEC5A on early macrophage-mediated inflammation in COPD progression.
Qingyang LiYu LiuXiaoyu WangChengshu XieXinyue MeiWeitao CaoWenhui GuanXinqing LinXiaohong XieChengzhi ZhouErkang YiPublished in: Cellular and molecular life sciences : CMLS (2024)
Chronic obstructive pulmonary disease (COPD) is a complex syndrome with poorly understood mechanisms driving its early progression (GOLD stages 1-2). Elucidating the genetic factors that influence early-stage COPD, particularly those related to airway inflammation and remodeling, is crucial. This study analyzed lung tissue sequencing data from patients with early-stage COPD (GSE47460) and smoke-exposed mice. We employed Weighted Gene Co-Expression Network Analysis (WGCNA) and machine learning to identify potentially pathogenic genes. Further analyses included single-cell sequencing from both mice and COPD patients to pinpoint gene expression in specific cell types. Cell-cell communication and pseudotemporal analyses were conducted, with findings validated in smoke-exposed mice. Additionally, Mendelian randomization (MR) was used to confirm the association between candidate genes and lung function/COPD. Finally, functional validation was performed in vitro using cell cultures. Machine learning analysis of 30 differentially expressed genes identified 8 key genes, with CLEC5A emerging as a potential pathogenic factor in early-stage COPD. Bioinformatics analyses suggested a role for CLEC5A in macrophage-mediated inflammation during COPD. Two-sample Mendelian randomization linked CLEC5A single nucleotide polymorphisms (SNPs) with Forced Expiratory Volume in One Second (FEV1), FEV1/Forced Vital Capacity (FVC) and early/later on COPD. In vitro, the knockdown of CLEC5A led to a reduction in inflammatory markers within macrophages. Our study identifies CLEC5A as a critical gene in early-stage COPD, contributing to its pathogenesis through pro-inflammatory mechanisms. This discovery offers valuable insights for developing early diagnosis and treatment strategies for COPD and highlights CLEC5A as a promising target for further investigation.
Keyphrases
- chronic obstructive pulmonary disease
- lung function
- early stage
- single cell
- genome wide
- cystic fibrosis
- air pollution
- machine learning
- gene expression
- network analysis
- oxidative stress
- dna methylation
- cell therapy
- stem cells
- rna seq
- computed tomography
- copy number
- poor prognosis
- genome wide identification
- intensive care unit
- high throughput
- adipose tissue
- squamous cell carcinoma
- chronic kidney disease
- small molecule
- end stage renal disease
- newly diagnosed
- acute respiratory distress syndrome
- drug induced
- human health