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

• Published in: Nature communications 2024-11, Vol.15 (1), p.9575-18, Article 9575
• Main Authors: Cruz Tleugabulova, Mayra, Melo, Sandra P., Wong, Aaron, Arlantico, Alexander, Liu, Meizi, Webster, Joshua D., Lau, Julia, Lechner, Antonie, Corak, Basak, Hodgins, Jonathan J., Garlapati, Venkata S., De Simone, Marco, Korin, Ben, Avraham, Shimrit, Lund, Jessica, Jeet, Surinder, Reiss, Alexander, Bender, Hannah, Austin, Cary D., Darmanis, Spyros, Modrusan, Zora, Brightbill, Hans, Durinck, Steffen, Diamond, Michael S., Schneider, Christoph, Shaw, Andrey S., Nitschké, Maximilian
• Format: Article
• Language: English
• Subjects: 13/31; 45/91; 631/250/2504/342; 631/250/256/2516; 631/250/262; 631/250/347; 64/60; 692/420/2780/262; Alveoli; Animal models; Animals; Antibodies; Bleomycin; Bleomycin - toxicity; Bone marrow; CD9 antigen; Cells; COVID-19; COVID-19 - immunology; Disease Models, Animal; Female; Fibrosis; Homeostasis; Humanities and Social Sciences; Humans; Injuries; Kupffer cells; Lung - immunology; Lung - metabolism; Lung - pathology; Lung Injury - immunology; Lung Injury - metabolism; Lung Injury - pathology; Lungs; Macrophages; Macrophages - immunology; Macrophages - metabolism; Macrophages, Alveolar - immunology; Macrophages, Alveolar - metabolism; Male; Mice; Mice, Inbred C57BL; Microglia; Monocytes; Monocytes - immunology; Monocytes - metabolism; multidisciplinary; Notch protein; Phenotypes; Pulmonary Fibrosis - chemically induced; Pulmonary Fibrosis - immunology; Pulmonary Fibrosis - metabolism; Pulmonary Fibrosis - pathology; Receptor, Notch2 - genetics; Receptor, Notch2 - metabolism; Science; Science (multidisciplinary)
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-024-53700-9

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. Macrophages are pleiotropic and can have different functions and phenotypes. Here the authors show that a population of macrophages, previously described as pro-fibrotic, can be induced through Notch2 blockade and that in a mouse lung injury and fibrosis model this macrophage population does not promote inflammation or fibrosis.