Abstract
Little is known about the relative importance of monocyte and tissue-resident macrophages in the development of lung fibrosis. We show that specific genetic deletion of monocyte-derived alveolar macrophages after their recruitment to the lung ameliorated lung fibrosis, whereas tissue-resident alveolar macrophages did not contribute to fibrosis. Using transcriptomic profiling of flow-sorted cells, we found that monocyte to alveolar macrophage differentiation unfolds continuously over the course of fibrosis and its resolution. During the fibrotic phase, monocyte-derived alveolar macrophages differ significantly from tissue-resident alveolar macrophages in their expression of profibrotic genes. A population of monocyte-derived alveolar macrophages persisted in the lung for one year after the resolution of fibrosis, where they became increasingly similar to tissue- resident alveolar macrophages. Human homologues of profibrotic genes expressed by mouse monocyte-derived alveolar macrophages during fibrosis were up-regulated in human alveolar macrophages from fibrotic compared with normal lungs. Our findings suggest that selectively targeting alveolar macrophage differentiation within the lung may ameliorate fibrosis without the adverse consequences associated with global monocyte or tissue-resident alveolar macrophage depletion.
Original language | English (US) |
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Pages (from-to) | 2387-2404 |
Number of pages | 18 |
Journal | Journal of Experimental Medicine |
Volume | 214 |
Issue number | 8 |
DOIs | |
State | Published - Aug 1 2017 |
Funding
A.V. Misharin is supported by National Institutes of Health (NIH) National Institute of Arthritis and Musculoskeletal and Skin Diseases grant AR061593, an American Thoracic Society/Scleroderma Foundation research grant, Department of Defense grant PR141319, and a BD Bioscience immunology research grant. P.A. Reyfman is supported by Northwestern University's Lung Sciences Training Program (5T32 HL076139-13). C.M. Cuda is supported by NIH grant AR064313. S. Chiu is supported by Northwestern Universitys Transplant Surgery Scientist Training Program (NIH grant T32 DK077662) and the American Society for Transplant Surgery Foundation. A. Bharat is supported by NIH grant HL125940 and matching funds from Thoracic Surgery Foundation, a research grant from the Society of University Surgeons, and an American Association of Thoracic Surgery John H. Gibbon Jr. Research Scholarship. B.D. Singer is supported by NIH grant HL128867 and the Parker B. Francis Research Opportunity Award. J.I. Sznajder is supported by NIH grants AG049665, HL048129, HL071643, and HL085534. G. Multlu is supported by NIH grants ES015024 and ES025644. K. Ridge is supported by NIH grants HL079190 and HL124664. G.R.S. Budinger is supported by NIH grants ES013995, HL071643, and AG049665; Veterans Administration grant BX000201, and Department of Defense grant PR141319. H. Perlman is supported by NIH grants AR064546, AG049665, and HL134375 and funds provided by Mabel Greene Myers Chair. The Northwestern University Flow Cytometry Facility and Center for Advanced Microscopy are supported by a National Cancer Institute cancer center support grant P30 CA060553 awarded to the Robert H. Lurie Comprehensive Cancer Center. The Genomics Computing Cluster is jointly supported by the Feinberg School of Medicine, the Center for Genetic Medicine, and Feinbergs Department of Biochemistry and Molecular Genetics, the Office of the Provost, the Office for Research, and Northwestern Information Technology and maintained and developed by Feinberg IT and Research Computing Group. The authors declare no competing financial interests. Author contributions: A.V. Misharin contributed to conceptualization, methodology, validation, formal analysis, investigation, resources, data curation, writing, visualization, supervision, project administration, and funding acquisition. L. Morales-Nebreda contributed to conceptualization, methodology, validation, formal analysis, investigation, data curation, writing, and visualization. P.A. Reyfman contributed to conceptualization, methodology, software, validation, formal analysis, investigation, data curation, writing, visualization, and supervision. T.J. Yacoub contributed to conceptualization, methodology, software, validation, formal analysis, data curation, writing, and visualization. C.M. Cuda contributed to conceptualization, methodology, validation, formal analysis, investigation, resources, data curation, and writing. H. Abdala- Valencia contributed to investigation, resources, data analysis, data curation, writing, visualization, and project administration. J.M. Walter contributed to formal analysis, investigation, data curation, writing, and visualization. A.C. McQuattie-Pimentel contributed to methodology, validation, formal analysis, investigation, data curation, and writing. C. Chen contributed to methodology, validation, formal analysis, investigation, and data curation. N. Joshi contributed to methodology, validation, formal analysis, investigation, and data curation. K.J.N. Williams contributed to methodology, validation, formal analysis, investigation, and data curation. M. Chi contributed to methodology, validation, formal analysis, investigation, and data curation. S. Chiu contributed to methodology, validation, formal analysis, investigation, data curation, and writing. F.J. Gonzalez-Gonzalez contributed to methodology, validation, formal analysis, investigation, and data curation. K. Gates contributed to methodology, validation, formal analysis, investigation, and data curation. A.P. Lam contributed to methodology, validation, formal analysis, investigation, and data curation. T.T. Nicholson contributed to investigation and data curation. P.J. Homan contributed to methodology, validation, formal analysis, investigation, and data curation. S. Soberanes contributed to methodology, validation, formal analysis, investigation, and data curation. S. Dominguez contributed to methodology, validation, and investigation. V.K. Morgan contributed to methodology, validation, investigation, and data curation. R. Saber contributed to validation, formal analysis, investigation, and data curation. A. Shaffer contributed to validation, formal analysis, investigation, and data curation. K.R. Anekalla contributed to methodology, software, validation, formal analysis, investigation, data curation, writing, and visualization. S.A. Marshall contributed to methodology, formal analysis, and investigation. M. Hinchcliff contributed to resources, data curation, writing, and supervision. A. Bharat contributed to resources, data curation, writing, and supervision. S.M. Bhorade contributed to resources, data curation, writing, and supervision. B.D. Singer and S. Berdnikovs contributed to methodology, validation, formal analysis, writing, and visualization. E.T. Bartom contributed to methodology, validation, software, and formal analysis. W.E. Balch contributed to conceptualization, resources, data curation, writing, supervision, and project administration. R.I. Morimoto contributed to conceptualization, resources, data curation, writing, and supervision, project administration. J.I. Sznajder contributed to conceptualization, resources, data curation, writing, supervision, and project administration. N.S. Chandel contributed to conceptualization, data curation, writing, and supervision. G.M. Mutlu contributed to conceptualization, resources, data curation, writing, and supervision. M. Jain contributed to conceptualization, data curation, writing, and supervision. C.J. Gottardi contributed to conceptualization, resources, writing, supervision, and project administration. K.M. Ridge contributed to conceptualization, resources, writing, supervision, and project administration. N. Bagheri contributed to conceptualization, methodology, formal analysis, resources, data curation, writing, and visualization. A. Shilatifard contributed to methodology, resources. GR.S. Budinger contributed to conceptualization, methodology, validation, formal analysis, investigation, resources, data curation, writing, visualization, supervision, project administration, and funding acquisition. H. Perlman contributed to conceptualization, methodology, validation, formal analysis, investigation, resources, data curation, writing, visualization, supervision, project administration, funding acquisition.
ASJC Scopus subject areas
- Immunology and Allergy
- Immunology