Nature Communications (Nov 2024)

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 De 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,
  • Maximilian Nitschké

DOI
https://doi.org/10.1038/s41467-024-53700-9
Journal volume & issue
Vol. 15, no. 1
pp. 1 – 18

Abstract

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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.