Abstract
Progressive pulmonary fibrosis (PPF) is a fatal lung condition characterized by persistent inflammation and progressive fibrotic remodeling. Monocyte-derived alveolar macrophages (Mo-AMs) are key drivers of fibrogenesis; however, the mechanisms underlying their persistence in fibrotic lungs remain unclear. Using lineage tracing and single-cell transcriptomics in a murine PPF model induced by continuous bleomycin infusion, we demonstrated the progressive accumulation of lineage-labeled Mo-AMs within fibrotic niches. Pharmacological depletion of monocytes and Mo-AMs attenuated fibrosis, underscoring their critical role in disease progression. Single-cell analysis identified a previously unrecognized Csf1-expressing neutrophil subpopulation. Functional experiments revealed that both neutrophil depletion and CSF1 neutralization significantly reduced the expansion of Mo-AMs, indicating that neutrophils and CSF1 signaling contribute to Mo-AM expansion during fibrotic progression. Consistent with these findings, bronchoalveolar lavage fluid from patients with pulmonary fibrosis contained elevated CSF1 levels, and CSF1-expressing neutrophils were detected within fibrotic lung regions. Together, these findings demonstrate that neutrophils and CSF1 signaling contribute to Mo-AM expansion during progressive pulmonary fibrosis.