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Research Article: S100A8 + S100A9 + transitional macrophages are associated with pulmonary fibrosis progression by integrating immunometabolism and fibrogenic crosstalk

Date Published: 2026-07-02

Abstract:
Idiopathic pulmonary fibrosis (IPF) is a progressive interstitial lung disease with limited therapeutic options. Although macrophage heterogeneity has been implicated in pathogenesis, the contribution of transitional macrophage states remains poorly understood. We integrated single?cell RNA?seq from 93 human lung specimens (44 IPF, 49 controls) and analyzed peripheral blood single?cell datasets (31 IPF, 17 controls). We examined differentiation trajectories and ligand–receptor networks and assessed metabolic programs. Functional relevance was evaluated in a bleomycin mouse model using histology, immunostaining, qRT?PCR, and tissue glutamine quantification. We identified an S100A8 + S100A9 + transitional macrophage population bridging FABP4 + MME + precursors and SPP1 + MMP9 + effector macrophages. These cells are associated with fibrogenesis through two interconnected mechanisms: epidermal growth factor (EGF)-mediated signaling to fibroblasts and alveolar epithelial cells, amplifying profibrotic communication; and glutamine metabolic reprogramming, marked by GLUL . In murine bleomycin induced fibrosis, these features emerged early, with elevated S100a8, S100a9, Fcna, Timp1 , and coincided with increased lung glutamine at day 14. Peripheral profiling confirmed concordant transcriptional changes in monocytes from IPF patients, supporting translational biomarker potential. S100A8 + S100A9 + macrophages might function as a druggable immune-metabolic hub in IPF. Targeting S100A8/A9, GLUL ?dependent glutamine flux, or EGFR?axis signaling may enable actionable paths for mechanism?based therapy. Furthermore, their peripheral molecular signature may offer a disease-specific biomarker platform for early diagnosis and therapeutic monitoring.

Introduction:
Idiopathic pulmonary fibrosis (IPF) is a progressive interstitial lung disease with limited therapeutic options. Although macrophage heterogeneity has been implicated in pathogenesis, the contribution of transitional macrophage states remains poorly understood.

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