Abstract
BACKGROUND: Macrophages play a crucial role in the progression of idiopathic pulmonary fibrosis (IPF). This study aims to identify a predictive signature based on macrophage-related genes to forecast patient prognosis and uncover potential therapeutic targets for IPF. METHODS: We analyzed single-cell transcriptomic and microarray data from the GEO database, exploring cellular variations in healthy controls, COPD, and IPF patients. CellChat and Monocle were utilized for analyzing cell interactions and pseudotime trajectories, respectively. Bioinformatics was used to identify differentially expressed genes, leading to the development of a gene signature via multivariate Cox regression, which was validated using ROC curves and an external dataset. The biological function of LGMN was investigated through in vivo and in vitro experiments. RESULTS: We observed a significant increase in monocyte-derived macrophages (MDMs) in patients with IPF, which negatively correlated with lung function. In IPF patients, interactions between macrophages and fibroblasts, as well as myofibroblasts, were both more frequent and intense compared to those observed in controls. Notably, the TGF-β1 signaling pathway was significantly activated in IPF, particularly within MDMs and myofibroblasts, leading to increased extracellular matrix (ECM) activity. We developed a gene signature associated with MDMs, which serves as an independent prognostic tool for IPF patients. In vitro experiments demonstrated elevated levels of LGMN in M2 macrophages, co-localizing with CD206 in fibrotic lung tissue. Treatment with RR-11a, a LGMN inhibitor, reduced TGF-β1 secretion from M2 macrophages, thereby diminishing communication between macrophages and fibroblasts and alleviating bleomycin-induced pulmonary fibrosis in mice. CONCLUSIONS: Our research establishes a gene signature associated with MDMs, which may aid clinicians in the personalized management of IPF. Additionally, we identify LGMN as a promoter of interaction between M2 macrophages and fibroblasts, suggesting its potential as a therapeutic target for IPF treatment.