Exosomal miR-125a-5p derived from silica-exposed macrophages induces fibroblast transdifferentiation

摘要

Silica particles can cause a systemic disease in workers termed lung silicosis, characterized by diffuse fibrosis. The development of lung silicosis involves various signaling pathway networks comprising numerous cell types and cytokines. As an important medium for communication between cells, exosomes have emerged as a hot research topic; however, the role of exosomal microRNAs (miRNAs) in silicosis remains unclear. In this study, we conducted high-throughput sequencing to generate exosomal miRNAs profiles from macrophages that were either exposed to silica or not. A total of 298 miRNAs were differentially expressed, with 155 up-regulated and 143 down-regulated. Highly conserved differentially expressed miRNAs were functionally annotated and analyzed to predict target genes. Among target interactions associated with the TGF-beta signaling pathway, miR-125a-5p and its putative target gene, Smurf1, were subjected to further research. As expected, levels of miR-125a-5p were upregulated in human serous exosomes and vitro, and inhibit the exosomal miR-125a-5p suppressed the expression of the fibrosis hallmarks. Besides, high levels of the miRNA led to upregulation of smooth muscle actin alpha and repression of Smurf1 in NIH-3T3 and MRC-5 cells. ID1 and SMAD1, downstream of TGF-beta signaling, were upregulated, indicating potential activation of this signaling pathway. These results contribute to understanding of the intercellular communication mediated by exosomal miRNAs and its critical role in fibroblast to myofibroblast transition and silicosis.