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

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

doi:10.1038/s41420-022-00831-x

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, FN1high, PLA2G7high, and MS4A6Ahigh macrophages with predominant M2 phenotype exhibited higher activity of inflammatory responses and para-inflammation than other macrophages. KRT17high basal-like epithelial cells were significantly increased in FHP, and showed higher ability to induce EMT. We identified roles for ACTA2high, COL1A1high, and PLA2G2Ahigh 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.

Highlights

Hypersensitivity pneumonitis (HP) is a complex syndrome with pulmonary alveolar unit inflammation or interstitial fibrosis caused by the inhalation of a variety of antigens in susceptible and sensitized individuals [1]
Through the integration of the expression profiling of surgical lung biopsy specimens from a patient with Fibrotic hypersensitivity pneumonitis (FHP) and published study databases including both bulk RNA-seq and scRNA-seq in Gene Expression Omnibus (GEO), we identified the contributions of specific cell subsets relevant to FHP
We identified epithelial cells, macrophages, endothelial cells, dendritic cells (DC), fibroblasts, T cells

Summary

Introduction

Hypersensitivity pneumonitis (HP) is a complex syndrome with pulmonary alveolar unit inflammation or interstitial fibrosis caused by the inhalation of a variety of antigens in susceptible and sensitized individuals [1]. HP was divided into two categories including fibrotic and non-fibrotic HP in Official ATS/JRS/ALAT Clinical Practice Guideline [2]. Compared with the incidence of idiopathic pulmonary fibrosis (IPF) which is approximately 4.6–16.3 per 100,000 person-years, the incidence of HP remains underrecognized [3]. Despite recent advances in diagnosis, classification, and therapeutic management of HP, FHP remains difficult to diagnose because of non-specific clinical syndrome and highresolution computed tomography (HRCT) features. The exposure of antigens has not been clearly identified in many HP cases [3, 4]. Bronchoalveolar lavage fluid (BALF) lymphocytosis and low CD4/ CD8 ratio are not consistently in fibrotic HP [3, 5, 6]

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Conclusion