Characterizing cellular heterogeneity in fibrotic hypersensitivity pneumonitis by single-cell transcriptional analysis

Junyi Wang; Lei Zhang; Li Luo; Ping He; Anying Xiong; Manling Jiang; Yao Liu; Shengbin Liu; Qin Ran; Dehong Wu; Ying Xiong; Xiang He; Guoping Li

doi:10.1038/s41420-022-00831-x

Characterizing cellular heterogeneity in fibrotic hypersensitivity pneumonitis by single-cell transcriptional analysis

Cell Death Discov. 2022 Jan 28;8(1):38. doi: 10.1038/s41420-022-00831-x.

Authors

Junyi Wang^#^{1

2

3}, Lei Zhang^#^{1

2

3}, Li Luo^#¹, Ping He², Anying Xiong^{1

2}, Manling Jiang^{1

2}, Yao Liu¹, Shengbin Liu¹, Qin Ran^{1

2}, Dehong Wu², Ying Xiong⁴, Xiang He^{5

6}, Guoping Li^{7

8

9}

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.
² Department of Pulmonary and Critical Care Medicine, Chengdu Third People's Hospital Branch of National Clinical Research Center for Respiratory Disease, Affiliated Hospital of ChongQing Medical University, Chengdu, China.
³ State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science & Technology, Taipa, Macau SAR, China.
⁴ Department of Pulmonary and Critical Care Medicine, Sichuan Friendship Hospital, Chengdu, China.
⁵ 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. xiangge530@hotmail.com.
⁶ Department of Pulmonary and Critical Care Medicine, Chengdu Third People's Hospital Branch of National Clinical Research Center for Respiratory Disease, Affiliated Hospital of ChongQing Medical University, Chengdu, China. xiangge530@hotmail.com.
⁷ 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. lzlgp@163.com.
⁸ Department of Pulmonary and Critical Care Medicine, Chengdu Third People's Hospital Branch of National Clinical Research Center for Respiratory Disease, Affiliated Hospital of ChongQing Medical University, Chengdu, China. lzlgp@163.com.
⁹ State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science & Technology, Taipa, Macau SAR, China. lzlgp@163.com.

^# Contributed equally.

Abstract

Fibrotic hypersensitivity pneumonitis (FHP) remains one of fatal interstitial pulmonary disease. Comprehensively dissecting the cellular heterogeneity of FHP paves the way for developing general gene therapeutic solutions for FHP. Here, utilizing an integrated strategy based on scRNA-seq, scTCR-seq, and bulk RNA-seq analysis of FHP profiles, we identified ten major cell types and 19 unique subtypes. FHP exhibited higher features of EMT and inflammation-promoting than normal control. In distinct subsets of lung macrophages in FHP, FN1^high, PLA2G7^high, and MS4A6A^high macrophages with predominant M2 phenotype exhibited higher activity of inflammatory responses and para-inflammation than other macrophages. KRT17^high basal-like epithelial cells were significantly increased in FHP, and showed higher ability to induce EMT. We identified roles for ACTA2^high, COL1A1^high, and PLA2G2A^high fibroblasts in FHP, which were significantly related to interstitial fibrosis. NK cells and KLRG1⁺ effector CD8⁺ T cells had greater activity in inflammation-promoting. Our results provide a comprehensive portrait of cellular heterogeneity in FHP, and highlight the indispensable role of cell subpopulations in shaping the complexity and heterogeneity of FHP. These subpopulations are potentially key players for FHP pathogenesis.

Abstract

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