Silica Particles Trigger Pulmonary Fibrosis Act Through Cell-To-Cell Delivery of Exosomal Mir-107

Abstract

\n Background: Long-term exposure to inhalable silica particles may lead to a serious systemic pulmonary disease called silicosis. However, the role and mechanisms of exosomes in silicosis are not well understood. We previously reported that serum exosomal micro (mi) RNA profile was altered in pneumoconiosis patients and silica-exposed macrophages.This study was aimed to explore and verify the role of the exosomal miRNA in lung fibrosis when exposed to silica particles. Results: The RT-qPCR result revealed that the levels of the miR-107, miR-122-5p, miR-125a-5p, miR-126-5p, and miR-335-5p were elevated in serous exosomes of silicosis patients. A bioinformatics analysis predicted 5 potential interactions involving these miRNAs, with miR-107–cyclin-dependent kinase (CDK) 6 having the highest score. In a mouse model of silica particle-induced silicosis, miR-107 level in serum exosomes and lung tissue was increased during the development of fibrosis, while inhibition of miR-107 reduced pulmonary fibrosis. The number of exosomes secreted by macrophages exposed to silica particles was also increased and showed altered cargo composition, and showed a capacity to promote lung fibroblast transdifferentiation through a possible mechanism involving the delivery of miR-107 by macrophages to lung fibroblasts via exosomes, resulting in targeted inhibition of CDK6, reduced retinoblastoma protein phosphorylation, and inhibition of E2F1 and cell cycle progression. Conclusion: In summary, exosomal miR-107 derived from macrophages exposed to silica particles were transferred to pulmonary fibroblasts to trigger their transdifferentiation by targeting CDK6 and arresting cell cycle. These findings provide insight into the pathogenesis of silicosis and potential targets for intervention.