S100A8+S100A9+ transitional macrophages drive pulmonary fibrosis progression via EGF signaling and glutamine metabolism

Idiopathic pulmonary fibrosis (IPF) is a devastating, progressive interstitial lung disease with severely limited therapeutic options and a poor prognosis. Current standard-of-care treatments often fail to halt disease progression or significantly improve survival, highlighting an urgent need for novel, mechanism-based interventions. While macrophage heterogeneity is known to contribute to IPF pathogenesis, the specific roles of transitional macrophage states and their interplay with immunometabolism and fibrogenic pathways have remained largely uncharacterized. Understanding these cellular and molecular mechanisms could unveil critical druggable targets.

Researchers integrated single-cell RNA-sequencing data from 93 human lung specimens (44 IPF, 49 controls) and analyzed peripheral blood single-cell datasets from 31 IPF patients and 17 controls. They employed advanced bioinformatics to examine differentiation trajectories and ligand-receptor networks, assessing metabolic programs within identified cell populations. Functional relevance was further evaluated in a murine bleomycin-induced fibrosis model using histological analysis, immunostaining, qRT-PCR for gene expression, and tissue glutamine quantification to validate findings in vivo.

A distinct S100A8+S100A9+ transitional macrophage population was identified, bridging FABP4+MME+ precursors and SPP1+MMP9+ effector macrophages. These cells were strongly associated with fibrogenesis through two interconnected mechanisms. First, they mediated epidermal growth factor (EGF) signaling to fibroblasts and alveolar epithelial cells, significantly amplifying profibrotic communication. Second, they exhibited profound glutamine metabolic reprogramming, specifically marked by the enzyme GLUL. > In the murine bleomycin-induced fibrosis model, these fibrotic features emerged early, with elevated expression of S100a8, S100a9, Fcna, and Timp1, coinciding with a notable increase in lung glutamine levels by day 14. Peripheral blood profiling further confirmed concordant transcriptional changes in monocytes from IPF patients, supporting the translational potential of these findings as a biomarker.