Integrated analysis of single-cell and bulk RNA sequencing reveals pro-fibrotic PLA2G7high macrophages in pulmonary fibrosis

Junyi Wang; Manling Jiang; Anying Xiong; Lei Zhang; Li Luo; Yao Liu; Shengbin Liu; Qin Ran; Dehong Wu; Ying Xiong; Xiang He; Elaine Lai-Han Leung; Guoping Li

doi:10.1016/j.phrs.2022.106286

Integrated analysis of single-cell and bulk RNA sequencing reveals pro-fibrotic PLA2G7^high macrophages in pulmonary fibrosis

Pharmacol Res. 2022 Aug:182:106286. doi: 10.1016/j.phrs.2022.106286. Epub 2022 Jun 2.

Authors

Junyi Wang¹, Manling Jiang², Anying Xiong², Lei Zhang¹, Li Luo³, Yao Liu³, Shengbin Liu³, Qin Ran², Dehong Wu⁴, Ying Xiong⁵, Xiang He⁶, Elaine Lai-Han Leung⁷, Guoping Li⁸

Affiliations

¹ Laboratory of Allergy and Precision Medicine, Chengdu Institute of Respiratory Health, the Third People's Hospital of Chengdu, Affiliated Hospital of Southwest Jiaotong University, Chengdu, China; Department of Pulmonary and Critical Care Medicine, Chengdu Institute of Respiratory Health, Chengdu Third People's Hospital Branch of National Clinical Research Center for Respiratory Disease, Chengdu, China; State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science & Technology, Taipa, Macao Special Administrative Region of China.
² Laboratory of Allergy and Precision Medicine, Chengdu Institute of Respiratory Health, the Third People's Hospital of Chengdu, Affiliated Hospital of Southwest Jiaotong University, Chengdu, China; Department of Pulmonary and Critical Care Medicine, Chengdu Institute of Respiratory Health, Chengdu Third People's Hospital Branch of National Clinical Research Center for Respiratory Disease, Chengdu, China.
³ Laboratory of Allergy and Precision Medicine, Chengdu Institute of Respiratory Health, the Third People's Hospital of Chengdu, Affiliated Hospital of Southwest Jiaotong University, Chengdu, China.
⁴ Department of Pulmonary and Critical Care Medicine, Chengdu Institute of Respiratory Health, Chengdu Third People's Hospital Branch of National Clinical Research Center for Respiratory Disease, Chengdu, China.
⁵ Department of Pulmonary and Critical Care Medicine, Sichuan Friendship Hospital, Chengdu, China.
⁶ Laboratory of Allergy and Precision Medicine, Chengdu Institute of Respiratory Health, the Third People's Hospital of Chengdu, Affiliated Hospital of Southwest Jiaotong University, Chengdu, China; Department of Pulmonary and Critical Care Medicine, Chengdu Institute of Respiratory Health, Chengdu Third People's Hospital Branch of National Clinical Research Center for Respiratory Disease, Chengdu, China. Electronic address: hexiang@swjtu.edu.cn.
⁷ Faculty of Health Sciences, University of Macau, Taipa, Macao Special Administrative Region of China. Electronic address: lhleung@um.edu.mo.
⁸ Laboratory of Allergy and Precision Medicine, Chengdu Institute of Respiratory Health, the Third People's Hospital of Chengdu, Affiliated Hospital of Southwest Jiaotong University, Chengdu, China; Department of Pulmonary and Critical Care Medicine, Chengdu Institute of Respiratory Health, Chengdu Third People's Hospital Branch of National Clinical Research Center for Respiratory Disease, Chengdu, China. Electronic address: liguoping@swjtu.edu.cn.

PMID: 35662628
DOI: 10.1016/j.phrs.2022.106286

Abstract

Pulmonary fibrosis (PF) is the pathological change of end-stage interstitial lung diseases with high mortality and limited therapeutic options. Lung macrophages have distinct subsets with divergent functions, and play critical roles in the pathogenesis of PF. In this study, integrative analysis of lung single-cell and bulk RNA-seq data from patients with fibrotic hypersensitivity pneumonitis and idiopathic pulmonary fibrosis was utilized to identify particular macrophage subsets during the development of PF. We find a specific macrophage subpopulation highly expressing PLA2G7 in fibrotic lungs. We performed additional single-cell RNA-seq analysis to identify analogous macrophage population in bleomycin (BLM)-induced mouse pulmonary fibrosis models. By in vitro and in vivo experiments, we further reveal the pro-fibrotic role for this PLA2G7^high macrophage subset in fibroblast-to-myofibroblast transition (FMT) during pulmonary fibrosis. PLA2G7 promotes FMT via LPC/ATX/LPA/LPA2 axis in macrophages. Moreover, PLA2G7 is regulated by STAT1, and pharmacological inhibition of PLA2G7 by Darapladib ameliorates pulmonary fibrosis in BLM-induced mice. The results of this study support the view that PLA2G7^high macrophage subpopulation contributes importantly to the pathogenesis of PF, which provides a potential way for targeted therapy.

Keywords: Fibroblast-to-myofibroblast transition; Macrophage; PLA2G7; Pulmonary fibrosis; Single-cell RNA-seq.

Publication types

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

MeSH terms

1-Alkyl-2-acetylglycerophosphocholine Esterase* / adverse effects
1-Alkyl-2-acetylglycerophosphocholine Esterase* / genetics
1-Alkyl-2-acetylglycerophosphocholine Esterase* / metabolism
Animals
Bleomycin
Idiopathic Pulmonary Fibrosis* / chemically induced
Idiopathic Pulmonary Fibrosis* / genetics
Lung
Macrophages*
Mice
Mice, Inbred C57BL
Sequence Analysis, RNA
Single-Cell Analysis

Substances

Bleomycin
1-Alkyl-2-acetylglycerophosphocholine Esterase
Pla2g7 protein, mouse