A new integrative analysis of histopathology and single cell RNA-seq reveals the CCL5 mediated T and NK cell interaction with vascular cells in idiopathic pulmonary arterial hypertension

• Published in: Journal of translational medicine Vol. 22; no. 1; p. 502
• Main Authors: Li, Xincheng, Ma, Shuangshuang, Wang, Qi, Li, Yishan, Ji, Xiaofan, Liu, Jixiang, Ma, Jing, Wang, Yongbing, Zhang, Zhu, Zhang, Hong, Chen, Hong, Xi, Linfeng, Zhang, Yunxia, Xie, Wanmu, Sun, Lu, Fu, Zhihui, Yang, Peiran, Wang, Chen, Zhai, Zhenguo
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 26-05-2024; BioMed Central; BMC
• Subjects: Analysis; Animals; Care and treatment; Cell Communication - genetics; Cell-cell interaction; Chemokine CCL5 - genetics; Chemokine CCL5 - metabolism; Computational Biology; Diagnosis; Familial Primary Pulmonary Hypertension - genetics; Familial Primary Pulmonary Hypertension - metabolism; Familial Primary Pulmonary Hypertension - pathology; Gene expression; Gene Regulatory Networks; Humans; Inflammation; IPAH; Killer Cells, Natural - immunology; Killer Cells, Natural - metabolism; Lung - pathology; Male; Monocrotaline; Protein Interaction Maps - genetics; Protein-protein interactions; Pulmonary hypertension; Rats; Rats, Sprague-Dawley; RNA-Seq; Single-Cell Analysis; Single-cell RNA-sequencing; T-Lymphocytes - immunology; T-Lymphocytes - metabolism; China; Inflammation; Single-cell RNA-sequencing; Cell-cell interaction; IPAH
• ISSN: 1479-5876; 1479-5876
• DOI: 10.1186/s12967-024-05304-6

Inflammation and dysregulated immunity play vital roles in idiopathic pulmonary arterial hypertension (IPAH), while the mechanisms that initiate and promote these processes are unclear.
Transcriptomic data of lung tissues from IPAH patients and controls were obtained from the Gene Expression Omnibus database. Weighted gene co-expression network analysis (WGCNA), differential expression analysis, protein-protein interaction (PPI) and functional enrichment analysis were combined with a hemodynamically-related histopathological score to identify inflammation-associated hub genes in IPAH. The monocrotaline-induced rat model of pulmonary hypertension was utilized to confirm the expression pattern of these hub genes. Single-cell RNA-sequencing (scRNA-seq) data were used to identify the hub gene-expressing cell types and their intercellular interactions.
Through an extensive bioinformatics analysis, CXCL9, CCL5, GZMA and GZMK were identified as hub genes that distinguished IPAH patients from controls. Among these genes, pulmonary expression levels of Cxcl9, Ccl5 and Gzma were elevated in monocrotaline-exposed rats. Further investigation revealed that only CCL5 and GZMA were highly expressed in T and NK cells, where CCL5 mediated T and NK cell interaction with endothelial cells, smooth muscle cells, and fibroblasts through multiple receptors.
Our study identified a new inflammatory pathway in IPAH, where T and NK cells drove heightened inflammation predominantly via the upregulation of CCL5, providing groundwork for the development of targeted therapeutics.