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

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...

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Published in	Nature immunology Vol. 20; no. 2; pp. 163 - 172
Main Authors	Aran, Dvir, Looney, Agnieszka P., Liu, Leqian, Wu, Esther, Fong, Valerie, Hsu, Austin, Chak, Suzanna, Naikawadi, Ram P., Wolters, Paul J., Abate, Adam R., Butte, Atul J., Bhattacharya, Mallar
Format	Journal Article
Language	English
Published	New York Nature Publishing Group US 01.02.2019 Nature Publishing Group
Subjects	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
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ISSN	1529-2908 1529-2916 1529-2916
DOI	10.1038/s41590-018-0276-y

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Summary:	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.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23 D.A. developed SingleR and performed computational analysis of single cell data under the guidance of A.J.B.; A.P.L. performed in vivo and in vitro experiments under the guidance of M.B. and with the assistance of E.W. and S.C.; L.L. performed microfluidic capture of single cell transcriptomes, library preparation, and sequencing under the guidance of A.R.A.; V.F., A.H, and E.W. prepared breeding and experimental stocks of genetically modified mice and performed lung injury models under the guidance of M.B.; P.J.W. contributed acquisition, storage, and processing of human samples and, with R.P.N., acquired lung microarray data from mice with telomere dysfunction; D.A. prepared the figures. M.B. conceived of the work, supervised experimental planning and execution, and wrote the manuscript with input D.A., A.P.L, and L.L. Author contributions
ISSN:	1529-2908 1529-2916 1529-2916
DOI:	10.1038/s41590-018-0276-y