PT  - JOURNAL ARTICLE
AU  - Christina Morse
AU  - Tracy Tabib
AU  - John Sembrat
AU  - Kristina Buschur
AU  - Humberto Trejo Bittar
AU  - Eleanor Valenzi
AU  - Yale Jiang
AU  - Daniel J. Kass
AU  - Kevin Gibson
AU  - Wei Chen
AU  - Ana Mora
AU  - Panayiotis V. Benos
AU  - Mauricio Rojas
AU  - Robert Lafyatis
TI  - Proliferating SPP1/MERTK-expressing macrophages in idiopathic pulmonary fibrosis
AID  - 10.1183/13993003.02441-2018
DP  - 2019 Jan 01
TA  - European Respiratory Journal
PG  - 1802441
4099  - http://erj.ersjournals.com/content/early/2019/06/04/13993003.02441-2018.short
4100  - http://erj.ersjournals.com/content/early/2019/06/04/13993003.02441-2018.full
AB  - 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.FootnotesThis 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.