Abstract
A comprehensive understanding of the changes in gene expression in cell types involved in idiopathic pulmonary fibrosis (IPF) will shed light on the mechanisms underlying the loss of alveolar epithelial cells and development of honeycomb cysts and fibroblastic foci. We sought to understand changes in IPF lung cell transcriptomes and gain insight into innate immune aspects of pathogenesis.
We investigated IPF pathogenesis using single-cell RNA-sequencing of fresh lung explants, comparing human IPF fibrotic lower lobes reflecting late disease, upper lobes reflecting early disease and normal lungs.
IPF lower lobes showed increased fibroblasts, and basal, ciliated, goblet and club cells, but decreased alveolar epithelial cells, and marked alterations in inflammatory cells. We found three discrete macrophage subpopulations in normal and fibrotic lungs, one expressing monocyte markers, one highly expressing FABP4 and INHBA (FABP4hi), and one highly expressing SPP1 and MERTK (SPP1hi). SPP1hi macrophages in fibrotic lower lobes showed highly upregulated SPP1 and MERTK expression. Low-level local proliferation of SPP1hi macrophages in normal lungs was strikingly increased in IPF lungs.
Co-localisation and causal modelling supported the role for these highly proliferative SPP1hi macrophages in activation of IPF myofibroblasts in lung fibrosis. These data suggest that SPP1hi macrophages contribute importantly to lung fibrosis in IPF, and that therapeutic strategies targeting MERTK and macrophage proliferation may show promise for treatment of this disease.
Abstract
By single-cell RNA-sequencing we identify three discrete pulmonary macrophage subsets, including one expressing highly upregulated SPP1 and proliferating in fibrotic IPF lower lobes, accompanied by marked deposition of osteopontin in the matrix http://bit.ly/2wIRNqF
Footnotes
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Author contributions: C. Morse performed immunofluorescence; T. Tabib performed single-cell RNA-sequencing experiments and bioinformatics analyses; J. Sembrat procured human tissues; K. Buschur analysed data by graphical modelling; H. Trejo Bittar reviewed and confirmed lung pathology; Y. Jiang helped with bioinformatics analyses; D.J. Kass provided intellectual support; E. Valenzi and K. Gibson reviewed clinical data; P.V. Benos supervised graphical modelling; W. Chen supervised RNA-sequencing analysis; C. Morse, T. Tabib, A. Mora, M. Rojas and R. Lafyatis conceived and guided the study; R. Lafyatis wrote the manuscript. All authors reviewed, edited and approved the final manuscript.
Support statement: Research reported in this publication was supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases under award number 2P50 AR060780; National Institute for Heart, Lung, and Blood Institute under award number R01 HL123766, U01 HL137159, R01 HL131789 and U0 HL137159; and National Library of Medicine under award R01 LM012087 of the National Institutes of Health. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Funding information for this article has been deposited with the Crossref Funder Registry.
Conflict of interest: C. Morse has nothing to disclose.
Conflict of interest: T. Tabib has nothing to disclose.
Conflict of interest: J. Sembrat has nothing to disclose.
Conflict of interest: K. Buschur has nothing to disclose.
Conflict of interest: H. Trejo Bittar has nothing to disclose.
Conflict of interest: E. Valenzi has nothing to disclose.
Conflict of interest: Y. Jiang has nothing to disclose.
Conflict of interest: D.J. Kass reports grants from NIH, during the conduct of the study; grants from Regeneron, outside the submitted work.
Conflict of interest: K. Gibson has nothing to disclose.
Conflict of interest: W. Chen has nothing to disclose.
Conflict of interest: A. Mora has nothing to disclose.
Conflict of interest: P.V. Benos has nothing to disclose.
Conflict of interest: M. Rojas has nothing to disclose.
Conflict of interest: R. Lafyatis has nothing to disclose.
- Received January 3, 2019.
- Accepted May 18, 2019.
- Copyright ©ERS 2019
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