Identification of ACKR4 as an immune checkpoint in pulmonary arterial hypertension

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

doi:10.3389/fimmu.2023.1153573

Frontiers in Immunology (Jun 2023)

Identification of ACKR4 as an immune checkpoint in pulmonary arterial hypertension

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

Affiliations

Chen-Yu Jiang: Shanghai Clinical Research Center for Rare Pediatric Diseases, Shanghai Children’s Medical Center (SCMC), School of Medicine, Shanghai Jiao Tong University, Shanghai, China
Chen-Yu Jiang: 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
Li-Wei Wu: Shanghai Clinical Research Center for Rare Pediatric Diseases, Shanghai Children’s Medical Center (SCMC), School of Medicine, Shanghai Jiao Tong University, Shanghai, China
Li-Wei Wu: 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
Yi-Wei Liu: Shanghai Clinical Research Center for Rare Pediatric Diseases, Shanghai Children’s Medical Center (SCMC), School of Medicine, Shanghai Jiao Tong University, Shanghai, China
Yi-Wei Liu: 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
Bei Feng: Shanghai Clinical Research Center for Rare Pediatric Diseases, Shanghai Children’s Medical Center (SCMC), School of Medicine, Shanghai Jiao Tong University, Shanghai, China
Bei Feng: 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
Lin-Cai Ye: Shanghai Clinical Research Center for Rare Pediatric Diseases, Shanghai Children’s Medical Center (SCMC), School of Medicine, Shanghai Jiao Tong University, Shanghai, China
Lin-Cai Ye: 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
Xu Huang: Shanghai Clinical Research Center for Rare Pediatric Diseases, Shanghai Children’s Medical Center (SCMC), School of Medicine, Shanghai Jiao Tong University, Shanghai, China
Xu Huang: 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
Yang-Yang He: School of Pharmacy, Henan University, Kaifeng, Henan, China
Yi Shen: Shanghai Clinical Research Center for Rare Pediatric Diseases, Shanghai Children’s Medical Center (SCMC), School of Medicine, Shanghai Jiao Tong University, Shanghai, China
Yi Shen: 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
Yi-Fan Zhu: Shanghai Clinical Research Center for Rare Pediatric Diseases, Shanghai Children’s Medical Center (SCMC), School of Medicine, Shanghai Jiao Tong University, Shanghai, China
Yi-Fan Zhu: 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
Xing-Liang Zhou: Shanghai Clinical Research Center for Rare Pediatric Diseases, Shanghai Children’s Medical Center (SCMC), School of Medicine, Shanghai Jiao Tong University, Shanghai, China
Xing-Liang Zhou: 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
Dai-Ji Jiang: Shanghai Clinical Research Center for Rare Pediatric Diseases, Shanghai Children’s Medical Center (SCMC), School of Medicine, Shanghai Jiao Tong University, Shanghai, China
Dai-Ji Jiang: 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
Hai-Kun Qi: School of Biomedical Engineering, Shanghaitech University, Shanghai, China
Hao Zhang: Shanghai Clinical Research Center for Rare Pediatric Diseases, Shanghai Children’s Medical Center (SCMC), School of Medicine, Shanghai Jiao Tong University, Shanghai, China
Hao Zhang: 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
Yi Yan: Shanghai Clinical Research Center for Rare Pediatric Diseases, Shanghai Children’s Medical Center (SCMC), School of Medicine, Shanghai Jiao Tong University, Shanghai, China
Yi Yan: 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

DOI: https://doi.org/10.3389/fimmu.2023.1153573
Journal volume & issue: Vol. 14

Abstract

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ObjectiveInflammation 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.MethodsDifferentially 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.ResultsACKR4 (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.ConclusionsThe 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.

Published in Frontiers in Immunology

ISSN: 1664-3224 (Online)
Publisher: Frontiers Media S.A.
Country of publisher: Switzerland
LCC subjects: Medicine: Internal medicine: Specialties of internal medicine: Immunologic diseases. Allergy
Website: http://journal.frontiersin.org/journal/immunology

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