Monocyte-Derived LGMN⁺ Macrophages Divert Lung Injury Outcomes toward Fibrosis through Matrix Remodeling

Pulmonary fibrosis (PF) is a fatal interstitial lung disease characterized by excessive extracellular matrix deposition and irreversible architectural distortion. The mechanisms driving the transition from tissue repair to fibrosis are complex and remain poorly understood. By analyzing interpatient variation across 75 idiopathic PF lungs, we identified a conserved profibrotic macrophage subset, distinct from canonical M1/M2 or SPP1⁺ states, characterized by high legumain (LGMN) expression and enrichment of gene signatures implicated in leukocyte activation and matrix remodeling. LGMN ⁺ macrophages localize within fibroblastic foci and are associated with disease progression and poor prognosis. Lineage-tracing and RNA velocity analyses revealed that LGMN ⁺ macrophages arise from monocytes through fibroblast-derived macrophage colony-stimulating factor signaling, which activates Maf BZIP transcription factor B-dependent differentiation programs. Pharmacological inhibition or macrophage-specific deletion of Lgmn markedly attenuated bleomycin-induced lung fibrosis, reduced extracellular matrix accumulation, and improved lung architecture. LGMN activates cathepsin S to mediate degradation of basement membrane collagen IV, thereby disrupting the alveolar-capillary barrier. In parallel, secreted LGMN acts as a paracrine signal to activate fibroblasts and promote collagen I deposition, collectively fostering a profibrotic niche. Together, these findings establish LGMN as a macrophage effector that links immune activation to matrix remodeling, thereby driving the transition from tissue injury to fibrosis.