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Identification of a broadly fibrogenic macrophage subset induced by type 3 inflammation

Lookup NU author(s): Professor Andrew FisherORCiD, Dr Lee Borthwick

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Abstract

Copyright © 2023 Th Authors, some rights reserved.Macrophages are central orchestrators of the tissue response to injury, with distinct macrophage activation states playing key roles in fibrosis progression and resolution. Identifying key macrophage populations found in human fibrotic tissues could lead to new treatments for fibrosis. Here, we used human liver and lung singlecell RNA sequencing datasets to identify a subset of CD9+TREM2+ macrophages that express SPP1, GPNMB, FABP5, and CD63. In both human and murine hepatic and pulmonary fibrosis, these macrophages were enriched at the outside edges of scarring and adjacent to activated mesenchymal cells. Neutrophils expressing MMP9, which participates in the activation of TGF-β1, and the type 3 cytokines GM-CSF and IL-17A coclustered with these macrophages. In vitro, GM-CSF, IL-17A, and TGF-β1 drive the differentiation of human monocytes into macrophages expressing scar-associated markers. Such differentiated cells could degrade collagen IV but not collagen I and promote TGF-β1–induced collagen I deposition by activated mesenchymal cells. In murine models blocking GM-CSF, IL-17A or TGF-β1 reduced scar-associated macrophage expansion and hepatic or pulmonary fibrosis. Our work identifies a highly specific macrophage population to which we assign a profibrotic role across species and tissues. It further provides a strategy for unbiased discovery, triage, and preclinical validation of therapeutic targets based on this fibrogenic macrophage population.

Publication metadata

Author(s): Fabre T, Barron AMS, Christensen SM, Asano S, Bound K, Lech MP, Wadsworth MH, Chen X, Wang C, Wang J, McMahon J, Schlerman F, White A, Kravarik KM, Fisher AJ, Borthwick LA, Hart KM, Henderson NC, Wynn TA, Dower K

Publication type: Article

Publication status: Published

Journal: Science Immunology

Year: 2023

Volume: 8

Issue: 82

Print publication date: 01/04/2023

Online publication date: 07/04/2023

Acceptance date: 16/03/2023

ISSN (electronic): 2470-9468

Publisher: American Association for the Advancement of Science

URL: https://doi.org/10.1126/sciimmunol.add8945

DOI: 10.1126/sciimmunol.add8945

PubMed id: 37027478

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