Macrophage-derived MMP12 promotes fibrosis through sustained damage to endothelial cells

Xinbei Zhou; Cong Zhang; Shaoqi Yang; Liliang Yang; Wei Luo; Wei Zhang; Xinxin Zhang; Jie Chao

doi:10.1016/j.jhazmat.2023.132733

Macrophage-derived MMP12 promotes fibrosis through sustained damage to endothelial cells

J Hazard Mater. 2024 Jan 5:461:132733. doi: 10.1016/j.jhazmat.2023.132733. Epub 2023 Oct 6.

Authors

Xinbei Zhou¹, Cong Zhang¹, Shaoqi Yang¹, Liliang Yang², Wei Luo³, Wei Zhang², Xinxin Zhang², Jie Chao⁴

Affiliations

¹ Jiangsu Provincial Key Laboratory of Critical Care Medicine, Zhongda Hospital, Department of Physiology, School of Medicine, Southeast University, Nanjing, Jiangsu, 210009, China; Key Laboratory of Environmental Medicine Engineering, Ministry of Education, School of Public Health, Southeast University, Nanjing, Jiangsu, 210009, China.
² Jiangsu Provincial Key Laboratory of Critical Care Medicine, Zhongda Hospital, Department of Physiology, School of Medicine, Southeast University, Nanjing, Jiangsu, 210009, China.
³ Jiangsu Provincial Key Laboratory of Critical Care Medicine, Zhongda Hospital, Department of Physiology, School of Medicine, Southeast University, Nanjing, Jiangsu, 210009, China; Jiangsu Key Laboratory of Molecular and Functional Imaging, Department of Radiology, Zhongda Hospital, Medical School of Southeast University, Nanjing 210009, China.
⁴ Jiangsu Provincial Key Laboratory of Critical Care Medicine, Zhongda Hospital, Department of Physiology, School of Medicine, Southeast University, Nanjing, Jiangsu, 210009, China; Key Laboratory of Environmental Medicine Engineering, Ministry of Education, School of Public Health, Southeast University, Nanjing, Jiangsu, 210009, China; Jiangsu Key Laboratory of Molecular and Functional Imaging, Department of Radiology, Zhongda Hospital, Medical School of Southeast University, Nanjing 210009, China; School of Medicine, Xizang Minzu University, Xianyang, Shanxi, 712082, China. Electronic address: chaojie@seu.edu.cn.

PMID: 37816293
DOI: 10.1016/j.jhazmat.2023.132733

Abstract

Macrophages are essential for the maintenance of endothelial cell function. However, the potential impact and mechanisms of crosstalk between macrophages and endothelial cells during silicosis progression remain unexplored. To fill this knowledge gap, a mouse model of silicosis was established. Single cell sequencing, spatial transcriptome sequencing, western blotting, immunofluorescence staining, tube-forming and wound healing assays were used to explore the effects of silicon dioxide on macrophage-endothelial interactions. To investigate the mechanism of macrophage-mediated fibrosis, MMP12 was specifically inactivated using siRNA and pharmacological approaches, and macrophages were depleted using disodium chlorophosphite liposomes. Compared to the normal saline group, the silica dust group showed altered macrophage-endothelial interactions. Matrix metalloproteinase family member MMP12 was identified as a key mediator of the altered function of macrophage-endothelial interactions after silica exposure, which was accompanied by pro-inflammatory macrophage activation and fibrotic progression. By using ablation strategies, macrophage-derived MMP12 was shown to mediate endothelial cell dysfunction by accumulating on the extracellular matrix. During the inflammatory phase of silicosis, MMP12 secreted by pro-inflammatory macrophages caused decreased endothelial cell viability, reduced migration, decreased trans-endothelial resistance and increased permeability; while during the fibrotic phase, macrophage-derived MMP12 sustained endothelial cell injury through accumulation on the extracellular matrix.

Keywords: Extracellular matrix (ECM); Macrophage-endothelial interactions; Pulmonary fibrosis; Silicosis.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Endothelial Cells
Fibrosis
Macrophages
Matrix Metalloproteinase 12* / genetics
Matrix Metalloproteinase 12* / pharmacology
Mice
Silicon Dioxide / toxicity
Silicosis* / pathology

Substances

Matrix Metalloproteinase 12
Silicon Dioxide