Impaired Macrophage Lipid Handling Initiates Lung Fibrosis via Lipid-Mediated Fibroblast Activation.

RATIONALE: Macrophages are essential for lung homeostasis and repair after injury, yet they can also promote pathological remodeling. Although mechanisms that sustain fibrosis are increasingly well defined, the endogenous events that initiate fibrotic remodeling remain incompletely understood. OBJECTIVES: To determine whether macrophage lipid dysregulation is sufficient to initiate lung fibrosis and define the cellular and lipid-mediated mechanisms linking macrophage dysfunction to fibroblast activation. METHODS: We examined mice deficient in the intracellular sterol transporter ABCG1 and assessed the temporal relationship between macrophage lipid accumulation, collagen deposition, and fibrotic remodeling. Lipidomic profiling was performed on Abcg1-deficient macrophages and macrophages isolated during early experimental fibrosis. Candidate lipid species were tested for their ability to activate fibroblasts in vitro, and therapeutic interventions targeting macrophage cholesterol trafficking or fibroblast lipid uptake were evaluated in vivo. MEASUREMENTS AND MAIN RESULTS: Loss of ABCG1 caused lipid accumulation in alveolar macrophages early before collagen deposition and lung remodeling. Lipidomic analyses revealed conserved enrichment of polyunsaturated acyl tails within complex lipid species in Abcg1-deficient macrophages and macrophages from early-stage experimental fibrosis. These lipids directly activated fibroblasts and induced fibrotic gene expression in vitro. Restoration of macrophage cholesterol trafficking or inhibition of fibroblast lipid uptake prevented fibrotic remodeling in vivo. CONCLUSIONS: Macrophage cholesterol dysregulation is sufficient to initiate spontaneous lung fibrosis. These findings identify a lipid-mediated macrophage-fibroblast axis as an endogenous driver of fibrotic remodeling and suggest that targeting macrophage lipid handling or fibroblast lipid uptake may represent a therapeutic strategy in fibrotic lung disease.