Study on the Role of CX3CR1⁺ Macrophages in Regulating Stem Cell Plasticity during Pulmonary Fibrosis

Abstract

Chronic lung fibrosis involves sustained tissue remodeling and impaired epithelial regeneration, yet the immune mechanisms governing fibrotic niche dynamics remain poorly understood. In this study, we identify CX3CR1⁺ interstitial macrophages—monocyte-derived immune cells—as key modulators of the epithelial stem cell niche during chronic lung injury. Utilizing lineage tracing and APEX-based proximity labeling in murine models, we demonstrate that CX3CR1⁺ macrophages accumulate within fibrotic regions and form close spatial interactions with Krt8⁺ damage-associated transient progenitors (DATPs), other immune cells, and myofibroblasts. Unlike the transient recruitment observed in acute injury, chronic injury promotes their prolonged retention and spatial reorganization, potentially contributing to a stalled regenerative state. These findings position CX3CR1⁺ interstitial macrophages as spatially coordinated regulators of epithelial stem cell regeneration and highlight their potential as therapeutic targets in chronic pulmonary fibrosis.