Induction of a distinct macrophage population and protection from lung injury and fibrosis by Notch2 blockade
Macrophages are pleiotropic and diverse cells that populate all tissues of the body. Besides tissue-specific resident macrophages such as alveolar macrophages, Kupffer cells, and microglia, multiple organs harbor at least two subtypes of other resident macrophages at steady state. During certain circumstances, like tissue insult, additional subtypes of macrophages are recruited to the tissue from the monocyte pool. Previously, a recruited macrophage population marked by expression of Spp1, Cd9, Gpnmb, Fabp5, and Trem2, has been described in several models of organ injury and cancer, and has been linked to fibrosis in mice and humans. Here, we show that Notch2 blockade, given systemically or locally, leads to an increase in this putative pro-fibrotic macrophage in the lung and that this macrophage state can only be adopted by monocytically derived cells and not resident alveolar macrophages. Using a bleomycin and COVID-19 model of lung injury and fibrosis, we find that the expansion of these macrophages before lung injury does not promote fibrosis but rather appears to ameliorate it. This suggests that these damage-associated macrophages are not, by themselves, drivers of fibrosis in the lung.
Authors
- Antonie Lechner (ORCID: https://orcid.org/0000-0002-1636-3354)
- Aaron K. Wong (ORCID: https://orcid.org/0000-0002-7294-0646)
- Marco De Simone (ORCID: https://orcid.org/0000-0002-7593-8314)
- Jessica Lund
- Ben Korin (ORCID: https://orcid.org/0000-0001-8867-7902)
- Steffen Durinck
- Jonathan J. Hodgins (ORCID: https://orcid.org/0000-0002-0390-5599)
- Surinder Jeet (ORCID: https://orcid.org/0000-0002-0442-8579)
- Meizi Liu (ORCID: https://orcid.org/0000-0002-7633-3384)
- Spyros Darmanis (ORCID: https://orcid.org/0000-0003-4002-8158)
- Alexander Reiss (ORCID: https://orcid.org/0000-0002-1230-8032)
- Basak Corak (ORCID: https://orcid.org/0000-0002-8255-9793)
- Joshua D. Webster (ORCID: https://orcid.org/0000-0002-0014-1685)
- Venkata Garlapati (ORCID: https://orcid.org/0000-0002-5337-3551)
- Hannah Bender (ORCID: https://orcid.org/0000-0001-9458-4964)
- Sandra P. Melo
- Alexander Arlantico (ORCID: https://orcid.org/0009-0001-0535-2588)
- Cary D. Austin (ORCID: https://orcid.org/0000-0002-5388-7413)
- Shimrit Avraham (ORCID: https://orcid.org/0000-0001-6331-8401)
- Michael Diamond (ORCID: https://orcid.org/0000-0002-8791-3165)
- Zora Modrušan (ORCID: https://orcid.org/0009-0003-5647-5195)
- Christoph Schneider (ORCID: https://orcid.org/0000-0002-0452-2960)
- Mayra Cruz Tleugabulova (ORCID: https://orcid.org/0000-0001-8105-856X)
- Maximilian Nitschké
- Hans D. Brightbill (ORCID: https://orcid.org/0000-0002-2366-8375)
- Andréy S. Shaw (ORCID: https://orcid.org/0000-0001-5685-0272)
- J. Lau
Institutions
- University of Zurich (CH)
- Washington University in St. Louis (US)
- Gene Therapy Laboratory (FR)
- Institut thématique Génétique, génomique et bioinformatique (FR)
- Genomic Health (United States) (US)
Publication Details
- Journal
- Nature Communications
- Published
- 2024-11-06
- DOI
- https://doi.org/10.1038/s41467-024-53700-9
- Citations
- 25
- Primary Topic
- Immune cells in cancer
- Type
- article
- Field-Weighted Citation Impact
- 6.01
Funders
- National Science Foundation
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung
- National Institutes of Health
- Genentech