Macrophage-derived GPNMB trapped by fibrotic extracellular matrix promotes pulmonary fibrosis
Jing Wang1, Xinxin Zhang1, Min Long2
1Jiangsu Provincial Key Laboratory of Critical Care Medicine, Zhongda Hospital, Department of Physiology, School of Medicine, Southeast University, Nanjing, Jiangsu, 210009, China.
Abstract:
Pulmonary fibrosis (PF) is a form of progressive lung disease characterized by chronic inflammation and excessive extracellular matrix (ECM) deposition. However, the protein changes in fibrotic ECM during PF and their contribution to fibrosis progression are unclear. Here we show that changes in expression of ECM components and ECM remodeling had occurred in silica-instilled mice. The macrophage-derived glycoprotein nonmetastatic melanoma protein B (GPNMB) captured by fibrotic ECM may activate resident normal fibroblasts around the fibrotic foci. Functional experiments demonstrated the activation of fibroblasts in fibrotic ECM, which was alleviated by GPNMB-neutralizing antibodies or macrophage deletion in the ECM of silica-instilled mice. Moreover, the Serpinb2 expression level was increased in fibroblasts in fibrotic ECM, and the expression of CD44 was increased in silica-instilled mice. In conclusion, macrophage-derived GPNMB is trapped by fibrotic ECM during transport and may activate fibroblasts via the CD44/Serpinb2 pathway, thus leading to the further development of fibrosis.
Insights
Macrophage-derived glycoprotein nonmetastatic melanoma protein B (GPNMB) trapped in fibrotic lung tissue activates fibroblasts, driving pulmonary fibrosis (PF) progression via the CD44/Serpinb2 pathway.
Area of Science:
- Pulmonary Medicine
- Cell Biology
- Immunology
Background:
- Pulmonary fibrosis (PF) involves chronic inflammation and excessive extracellular matrix (ECM) deposition.
- The specific protein alterations within fibrotic ECM and their role in PF progression remain largely unknown.
Purpose of the Study:
- To investigate protein expression changes in fibrotic ECM during PF.
- To elucidate the mechanism by which ECM components contribute to fibroblast activation and fibrosis.
Main Methods:
- Silica-instillation model in mice to induce pulmonary fibrosis.
- Analysis of ECM component expression and remodeling.
- Functional assays to assess fibroblast activation.
- Administration of GPNMB-neutralizing antibodies and macrophage depletion.
Main Results:
- Silica-instilled mice exhibited altered ECM composition and remodeling.
- Macrophage-derived glycoprotein nonmetastatic melanoma protein B (GPNMB) was identified within the fibrotic ECM.
- GPNMB activation of resident fibroblasts was observed and could be inhibited by GPNMB-neutralizing antibodies or macrophage depletion.
- Increased expression of Serpinb2 in fibroblasts and CD44 in silica-instilled mice was noted.
Conclusions:
- Macrophage-derived GPNMB is sequestered by fibrotic ECM.
- GPNMB activates fibroblasts through the CD44/Serpinb2 pathway, promoting further fibrosis development.
