Lineage tracing reveals the origins and dynamics of macrophages in lung injury and repair.

Macrophages play a vital role in tissue repair and regeneration following injury. However, the cell fate, dynamic responses, and functions of macrophages from various origins during lung injury and repair are not fully understood. Here, we used genetic lineage tracing and scRNA-seq approaches to explore the temporal and spatial roles of tissue-resident and infiltrating macrophages during pulmonary fibrosis. We observed a sharp reduction in tissue-resident macrophages during the early inflammatory phase, with their numbers stabilizing during recovery. Monocytes contributed substantially to the macrophage population during the fibrotic phase, initially differentiating into interstitial macrophages and later transitioning into alveolar macrophages through a transient state. Genetic ablation of monocytes led to a reduction in the number of infiltrating macrophages and alleviated pulmonary fibrosis. Mechanistically, Notch signaling was negatively correlated with Wnt/β-catenin signaling in the regulation of monocyte recruitment and pulmonary fibrosis. Our study reveals the dynamic contributions and functions of macrophages from various sources in lung injury and regeneration.