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Proliferating SPP1/MERTK-expressing macrophages in idiopathic pulmonary fibrosis

Christina Morse, Tracy Tabib, John Sembrat, Kristina Buschur, Humberto Trejo Bittar, Eleanor Valenzi, Yale Jiang, Daniel J. Kass, Kevin Gibson, Wei Chen, Ana Mora, Panayiotis V. Benos, Mauricio Rojas, Robert Lafyatis
European Respiratory Journal 2019; DOI: 10.1183/13993003.02441-2018
Christina Morse
1Division of Rheumatology and Clinical Immunology
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Tracy Tabib
1Division of Rheumatology and Clinical Immunology
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John Sembrat
2Division of Pulmonary, Allergy and Critical Care, Department of Medicine
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Kristina Buschur
3Depatment of Computational and Systems Biology
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Humberto Trejo Bittar
4Department of Pathology
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Eleanor Valenzi
2Division of Pulmonary, Allergy and Critical Care, Department of Medicine
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Yale Jiang
5Division of Pulmonary Medicine, Allergy and Immunology, Department of Pediatrics; School of Medicine, University of Pittsburgh
6School of Medicine, Tsinghua University, Beijing, China
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Daniel J. Kass
2Division of Pulmonary, Allergy and Critical Care, Department of Medicine
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Kevin Gibson
2Division of Pulmonary, Allergy and Critical Care, Department of Medicine
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Wei Chen
5Division of Pulmonary Medicine, Allergy and Immunology, Department of Pediatrics; School of Medicine, University of Pittsburgh
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  • ORCID record for Wei Chen
Ana Mora
2Division of Pulmonary, Allergy and Critical Care, Department of Medicine
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Panayiotis V. Benos
3Depatment of Computational and Systems Biology
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Mauricio Rojas
2Division of Pulmonary, Allergy and Critical Care, Department of Medicine
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Robert Lafyatis
1Division of Rheumatology and Clinical Immunology
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  • For correspondence: lafyatis@pitt.edu
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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 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.

Footnotes

This manuscript has recently been accepted for publication in the European Respiratory Journal. It is published here in its accepted form prior to copyediting and typesetting by our production team. After these production processes are complete and the authors have approved the resulting proofs, the article will move to the latest issue of the ERJ online. Please open or download the PDF to view this article.

Conflict of interest: Ms. Morse has nothing to disclose.

Conflict of interest: Ms. Tabib has nothing to disclose.

Conflict of interest: Dr. Sembrat has nothing to disclose.

Conflict of interest: Ms. Buschur has nothing to disclose.

Conflict of interest: Dr. Valenzi has nothing to disclose.

Conflict of interest: Dr. Jiang has nothing to disclose.

Conflict of interest: Dr. Kass reports grants from NIH, during the conduct of the study; grants from Regeneron, outside the submitted work; .

Conflict of interest: Dr. Gibson has nothing to disclose.

Conflict of interest: Dr. Chen has nothing to disclose.

Conflict of interest: Dr. Mora has nothing to disclose.

Conflict of interest: Dr. Benos has nothing to disclose.

Conflict of interest: Dr. Rojas has nothing to disclose.

Conflict of interest: Dr. Lafyatis has nothing to disclose.

Conflict of interest: Dr. Trejo Bittar has nothing to disclose.

This is a PDF-only article. Please click on the PDF link above to read it.

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Proliferating SPP1/MERTK-expressing macrophages in idiopathic pulmonary fibrosis
Christina Morse, Tracy Tabib, John Sembrat, Kristina Buschur, Humberto Trejo Bittar, Eleanor Valenzi, Yale Jiang, Daniel J. Kass, Kevin Gibson, Wei Chen, Ana Mora, Panayiotis V. Benos, Mauricio Rojas, Robert Lafyatis
European Respiratory Journal Jan 2019, 1802441; DOI: 10.1183/13993003.02441-2018

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Proliferating SPP1/MERTK-expressing macrophages in idiopathic pulmonary fibrosis
Christina Morse, Tracy Tabib, John Sembrat, Kristina Buschur, Humberto Trejo Bittar, Eleanor Valenzi, Yale Jiang, Daniel J. Kass, Kevin Gibson, Wei Chen, Ana Mora, Panayiotis V. Benos, Mauricio Rojas, Robert Lafyatis
European Respiratory Journal Jan 2019, 1802441; DOI: 10.1183/13993003.02441-2018
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