Macrophage-derived GPNMB Trapped by Fibrotic Extracellular Matrix Promotes Pulmonary Fibrosis

Abstract

Pulmonary fibrosis (PF) is a form of progressive lung disease characterized by chronic inflammation and excessive extracellular matrix (ECM) deposition. The pulmonary ECM undergoes profound changes during fibrosis. However, the protein changes that occur in fibrotic ECM during silica-induced progressive PF and their contribution to fibrosis progression are unclear. Here, we established a model of progressive PF induced by silica, observed the effect of fibrotic ECM on normal fibroblast activation and explored the possible mechanism. Proteomic analysis of the ECM revealed that obvious changes in the expression of ECM components and ECM remodeling occurred. Single-cell RNA sequencing (scRNA-seq) combined with spatial transcriptomics revealed that during transport, macrophage-derived glycoprotein nonmetastatic melanoma protein B (GPNMB) captured by fibrotic ECM may activate resident normal fibroblasts around fibrotic foci. Functional experiments showed activation of normal fibroblasts in fibrotic ECM, which was alleviated by GPNMB-neutralizing antibodies or macrophage deletion in the ECM of silica-instilled mice, implying that macrophage-derived GPNMB may contribute to progressive PF. Transcriptome analysis showed that the Serpinb2 expression level was increased in fibroblasts in fibrotic ECM, and the expression of CD44, a cell receptor for GPNMB, was increased in mice after silica instillation according to scRNA-seq combined with spatial transcriptomics. Therefore, macrophage-derived GPNMB is trapped by fibrotic ECM during transport and may activate fibroblasts via the CD44/Serpinb2 pathway, leading to further development of fibrosis.

Insights into the heterogeneity of the tumor microenvironment in lung adenocarcinoma and squamous carcinoma through single‐cell transcriptomic analysis: Implications for distinct immunotherapy outcomes

“…40 GPNMB also regulates fibroblast activation and lung fibrosis. 41 The correlation between GPNMB and CAFs was validated in TCGA cohort (see Supporting information, Figure S3G). Elevated levels of shed GPNMB correlate with resistance to immune checkpoint blockade (ICB) therapy and their relationship with CAFs in advanced NSCLC, 42 suggesting GPNMB as a potential therapeutic target.…”