Department of Cancer Immunology, Genentech Research and Early Development, South San Francisco, CA, 94080, USA.
Department of Bioinformatics, Genentech Research and Early Development, South San Francisco, CA, 94080, USA.
Nat Commun. 2024 Nov 6;15(1):9575. 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.
巨噬细胞是多功能、多样化的细胞，存在于人体的所有组织中。除了组织特异性常驻巨噬细胞，如肺泡巨噬细胞、枯否细胞和小胶质细胞外，多个器官在稳态时至少还存在两种其他常驻巨噬细胞亚型。在某些情况下，如组织损伤，单核细胞池中的额外巨噬细胞亚群会被招募到组织中。此前，在几种器官损伤和癌症模型中，已经描述了一种表达 Spp1、Cd9、Gpnmb、Fabp5 和 Trem2 的募集性巨噬细胞群体，并与小鼠和人类的纤维化有关。在这里，我们表明，系统或局部给予 Notch2 阻断剂会导致肺中这种假定的促纤维化巨噬细胞增加，而且这种巨噬细胞状态只能被单核细胞衍生的细胞采用，而不是常驻肺泡巨噬细胞。使用博来霉素和 COVID-19 肺损伤和纤维化模型，我们发现，肺损伤前这些巨噬细胞的扩张并没有促进纤维化，反而似乎改善了纤维化。这表明这些损伤相关巨噬细胞本身并不是肺纤维化的驱动因素。
