Identification of ACKR4 as an immune checkpoint in pulmonary arterial hypertension

Chen-Yu Jiang; Li-Wei Wu; Yi-Wei Liu; Bei Feng; Lin-Cai Ye; Xu Huang; Yang-Yang He; Yi Shen; Yi-Fan Zhu; Xing-Liang Zhou; Dai-Ji Jiang; Hai-Kun Qi; Hao Zhang; Yi Yan

doi:10.3389/fimmu.2023.1153573

Identification of ACKR4 as an immune checkpoint in pulmonary arterial hypertension

Front Immunol. 2023 Jun 28:14:1153573. doi: 10.3389/fimmu.2023.1153573. eCollection 2023.

Authors

Chen-Yu Jiang^{1

2}, Li-Wei Wu^{1

2}, Yi-Wei Liu^{1

2}, Bei Feng^{1

2}, Lin-Cai Ye^{1

2}, Xu Huang^{1

2}, Yang-Yang He³, Yi Shen^{1

2}, Yi-Fan Zhu^{1

2}, Xing-Liang Zhou^{1

2}, Dai-Ji Jiang^{1

2}, Hai-Kun Qi⁴, Hao Zhang^{1

2}, Yi Yan^{1

2}

Affiliations

¹ Shanghai Clinical Research Center for Rare Pediatric Diseases, Shanghai Children's Medical Center (SCMC), School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
² Heart Center and Shanghai Institute of Pediatric Congenital Heart Disease, Shanghai Children's Medical Center (SCMC), School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
³ School of Pharmacy, Henan University, Kaifeng, Henan, China.
⁴ School of Biomedical Engineering, Shanghaitech University, Shanghai, China.

Abstract

Objective: Inflammation is recognized as a contributor in the development of pulmonary arterial hypertension (PAH), and the recruitment and functional capacity of immune cells are well-orchestrated by chemokines and their receptors. This study is aimed at identification of critical chemokines in the progression of PAH via transcriptomic analysis.

Methods: Differentially expressed genes (DEGs) from lungs of PAH patients were achieved compared to controls based on Gene Expression Omnibus (GEO) database. Gene set enrichment analysis (GSEA) was applied for functional annotation and pathway enrichement. The abundance of immune cells was estimated by the xCell algorithm. Weighted correlation network analysis (WGCNA) was used to construct a gene expression network, based on which a diagnostic model was generated to determine its accuracy to distinguish PAH from control subjects. Target genes were then validated in lung of hypoxia-induce pulmonary hypertension (PH) mouse model.

Results: ACKR4 (atypical chemokine receptor 4) was downregulated in PAH lung tissues in multiple datasets. PAH relevant biological functions and pathways were enriched in patients with low-ACKR4 level according to GSEA enrichment analysis. Immuno-infiltration analysis revealed a negative correlation of activated dendritic cells, Th1 and macrophage infiltration with ACKR4 expression. Three gene modules were associated with PAH via WGCNA analysis, and a model for PAH diagnosis was generated using CXCL12, COL18A1 and TSHZ2, all of which correlated with ACKR4. The ACKR4 expression was also downregulated in lung tissues of our experimental PH mice compared to that of controls.

Conclusions: The reduction of ACKR4 in lung tissues of human PAH based on transcriptomic data is consistent with the alteration observed in our rodent PH. The correlation with immune cell infiltration and functional annotation indicated that ACKR4 might serve as a protective immune checkpoint for PAH.

Keywords: atypical chemokine receptor 4; chemokines; immune; pulmonary arterial hypertension; transcriptomics.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Familial Primary Pulmonary Hypertension
Gene Expression Profiling
Humans
Hypertension, Pulmonary* / genetics
Lung
Mice
Pulmonary Arterial Hypertension* / genetics

Grants and funding

This work was supported by the Project of National Natural Science Foundation of China (U20A2018), the Project of Shanghai Municipal Science and Technology Commission (20MC1920400), the National Key Research and Development Program of China (2022YFC2703102), Projects of National Natural Science Foundation of China (82200065, 82241007), Shanghai Pujiang Program (22PJ1410100), Young Talent Program of Shanghai Municipal Health Commission (2022YQ070) and Innovative research team of high-level local universities in Shanghai.