Midkine, a novel MCP-1 activator mediated PM2.5-aggravated experimental pulmonary fibrosis

Exposure to fine particulate matter (PM2.5) is associated with increased morbidity and mortality among patients with idiopathic pulmonary fibrosis (IPF). Pathological alterations in IPF typically originate in the subpleural regions of the lungs. However, it was unclear how PM2.5 affected subpleural pulmonary fibrosis. In this study, atmospheric PM2.5 and carbon blacks were utilized as representative particulate matter to investigate these effects. Mouse models and cell models were made to investigate macrophage chemotaxis changes under PM2.5 exposure in vivo and in vitro. The findings indicated that PM2.5 promoted macrophage aggregation in the subpleural region of lung and aggravated bleomycin-induced pulmonary fibrosis in mice. At the same time, we uncovered for the first time that PM2.5 exposure led to an upregulation of midkine, which subsequently enhanced the production of monocyte chemotactic protein-1 (MCP-1) through the cell surface receptor Syndecan 4 (SDC4) in pleural mesothelial cells (PMCs), thereby, inducing macrophage aggregation in subpleural region of lung. Furthermore, our results indicated that PM2.5 and bleomycin facilitated macrophage M1 polarization and the production of profibrotic inflammatory factors, culminating in fibrotic alterations in PMCs, lung fibroblasts, and alveolar epithelial cells. Finally, we demonstrated that inhibition of midkine ameliorated lung function and mitigated pulmonary fibrosis in vivo. In conclusion, our findings elucidated that midkine acted as a novel MCP-1 activator, mediating PM2.5-aggravated experimental pulmonary fibrosis, and suggested that the midkine/SDC4/MCP-1 signal should be a new therapeutic target for the treatment of PM2.5-related IPF.