Abstract Rationale Pulmonary fibrosis arises from dysregulated tissue repair concurrent with chronic inflammation. Macrophages critically orchestrate tissue repair and immune responses, yet how lipid-associated macrophages (LAMs) functionally adapt during fibrosis remains unclear. Objective To determine the role of lipid-associated macrophages (LAMs) in lung injury repair and fibrosis Method and Results We demonstrated that LAM accumulation positively correlates with fibrosis severity across multiple murine models. Pulmonary macrophage transplantation revealed that persistent LAMs spontaneously initiate fibrosis, while APOE+/+ alveolar macrophages (AMs) were essential for fibrosis resolution. Cholesterol constitutes the dominant lipid in LAMs, primarily originating from stressed AT2 cells. In vitro, free cholesterol (FC) initially induced proinflammatory phenotypes but progressively drove LAM transition. Transcriptional profiling identified cholesterol oxidation as a key metabolic adaptation during LAM differentiation, with Cholesterol 25-Hydroxylase (CH25H) as the pivotal responder. Furthermore, 25-Hydroxycholesterol (25-HC) directly activated LAM gene expression in an LXRα-dependent manner. Both FC and 25-HC promoted LAM buildup and lung fibrosis in mice with divergent kinetics. While therapeutically enhancing APOE- and ABCG1-mediated reverse cholesterol transport (RCT) reduced LAM accumulation and attenuated fibrosis by thyroid hormone (T3). These findings define LAM transition and functions, revealing cholesterol metabolism as tunable targets for modulating macrophage fate in lung fibrosis. Conclusion Cholesterol oxidation into 25-HC governs the inflammatory macrophage-to-LAM transition, orchestrating lung repair and fibrosis. This abstract is funded by: NSFC32570921
Wang et al. (Fri,) studied this question.