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. Recently, 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 linked to fibrosis in mice and humans. Here, we show that Notch2 blockade given systemically or locally led to an increase in this putative pro-fibrotic macrophage in the lung. Single cell RNA sequencing suggested that the newly arising population derived from monocytes when Notch2 blockade was systemic or derived from alveolar macrophages when Notch2 blockade was local. Unexpectedly, using a bleomycin and COVID19 model of lung injury and fibrosis, we found that the expansion of these macrophages before lung injury ameliorated rather than promoted fibrosis. This suggests that these damage-associated macrophages are not drivers of fibrosis in the lung.