Journal Article

Reference-based analysis of lung single-cell sequencing reveals a transitional profibrotic macrophage

Liu, Leqian, Fong, Valerie, Wu, Esther, Naikawadi, Ram P., Wolters, Paul J., Abate, Adam R., Aran, Dvir, Looney, Agnieszka P., Hsu, Austin, Chak, Suzanna, Bhattacharya, Mallar, Butte, Atul J.

2019

Overview

Tissue fibrosis is a major cause of mortality that results from the deposition of matrix proteins by an activated mesenchyme. Macrophages accumulate in fibrosis, but the role of specific subgroups in supporting fibrogenesis has not been investigated in vivo. Here, we used single-cell RNA sequencing (scRNA-seq) to characterize the heterogeneity of macrophages in bleomycin-induced lung fibrosis in mice. A novel computational framework for the annotation of scRNA-seq by reference to bulk transcriptomes (SingleR) enabled the subclustering of macrophages and revealed a disease-associated subgroup with a transitional gene expression profile intermediate between monocyte-derived and alveolar macrophages. These CX3CR1 + SiglecF + transitional macrophages localized to the fibrotic niche and had a profibrotic effect in vivo. Human orthologs of genes expressed by the transitional macrophages were upregulated in samples from patients with idiopathic pulmonary fibrosis. Thus, we have identified a pathological subgroup of transitional macrophages that are required for the fibrotic response to injury. Using scRNA-seq analysis, Bhattacharya and colleagues identify a subset of profibrotic lung macrophages that have a gene expression signature intermediate between those of monocytes and alveolar macrophages.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: 631/1647/2017 / 631/1647/767/1424 / 631/250/2504/342/1927 / 692/699 / Alveoli / Analysis / Animals / Antigens, Differentiation, Myelomonocytic - genetics / Antigens, Differentiation, Myelomonocytic - immunology / Antigens, Differentiation, Myelomonocytic - metabolism / Biochemistry / Biomedical and Life Sciences / Biomedicine / Bleomycin / Bleomycin - immunology / Cells, Cultured / Computer applications / CX3C Chemokine Receptor 1 - genetics / CX3C Chemokine Receptor 1 - immunology / CX3C Chemokine Receptor 1 - metabolism / CX3CR1 protein / Disease Models, Animal / Female / Fibrosis / Gene expression / Gene Expression Profiling - methods / Genes / Genomes / Health aspects / Heterogeneity / Humans / Idiopathic Pulmonary Fibrosis - immunology / Idiopathic Pulmonary Fibrosis - pathology / Immunology / Infectious Diseases / Lung - cytology / Lung - immunology / Lung - pathology / Lung diseases / Macrophage Activation / Macrophages / Macrophages, Alveolar - immunology / Macrophages, Alveolar - metabolism / Male / Mesenchyme / Mice / Monocytes / Mortality / Proteins / Pulmonary fibrosis / Respiratory tract diseases / Ribonucleic acid / RNA / RNA sequencing / Sequence Analysis, RNA - methods / Single-Cell Analysis - methods / Up-Regulation