Induction of a distinct macrophage population and protection from lung injury and fibrosis by Notch2 blockade

Mayra Cruz Tleugabulova, Sandra P. Melo (), Aaron Wong, Alexander Arlantico, Meizi Liu, Joshua D. Webster, Julia Lau, Antonie Lechner, Basak Corak, Jonathan J. Hodgins, Venkata S. Garlapati, Marco Simone, Ben Korin, Shimrit Avraham, Jessica Lund, Surinder Jeet, Alexander Reiss, Hannah Bender, Cary D. Austin, Spyros Darmanis, Zora Modrusan, Hans Brightbill, Steffen Durinck, Michael S. Diamond, Christoph Schneider, Andrey S. Shaw () and Maximilian Nitschké ()
Additional contact information
Mayra Cruz Tleugabulova: Genentech Research and Early Development
Sandra P. Melo: Genentech Research and Early Development
Aaron Wong: Genentech Research and Early Development
Alexander Arlantico: Genentech Research and Early Development
Meizi Liu: Washington University School of Medicine
Joshua D. Webster: Genentech Research and Early Development
Julia Lau: Genentech Research and Early Development
Antonie Lechner: University of Zürich
Basak Corak: University of Zürich
Jonathan J. Hodgins: Genentech Research and Early Development
Venkata S. Garlapati: Genentech Research and Early Development
Marco Simone: Genentech Research and Early Development
Ben Korin: Genentech Research and Early Development
Shimrit Avraham: Genentech Research and Early Development
Jessica Lund: Genentech Research and Early Development
Surinder Jeet: Genentech Research and Early Development
Alexander Reiss: Genentech Research and Early Development
Hannah Bender: Genentech Research and Early Development
Cary D. Austin: Genentech Research and Early Development
Spyros Darmanis: Genentech Research and Early Development
Zora Modrusan: Genentech Research and Early Development
Hans Brightbill: Genentech Research and Early Development
Steffen Durinck: Genentech Research and Early Development
Michael S. Diamond: Washington University School of Medicine
Christoph Schneider: University of Zürich
Andrey S. Shaw: Genentech Research and Early Development
Maximilian Nitschké: Genentech Research and Early Development

Nature Communications, 2024, vol. 15, issue 1, 1-18

Abstract: Abstract 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.

Date: 2024
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DOI: 10.1038/s41467-024-53700-9

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