Exosomal miR-125a-5p regulates T lymphocyte subsets to promote silica-induced pulmonary fibrosis by targeting TRAF6

Silicosis caused by long-term inhalation of crystalline silica during occupational activities seriously threatens the health of occupational populations. Imbalances in T helper 1(Th1), Th2, Th17, and regulatory T cells (Tregs) promote the development of pulmonary silicosis. Exosomes and their contents, especially microRNAs (miRNAs), represent a new type of intercellular signal transmission mediator related to various diseases including pulmonary fibrosis. However, whether exosomal miRNAs can affect the progression of silicosis by regulating T cell differentiation remains to be determined. To test this hypothesis, we established a miR-125a-5p antagomir mouse model and examined changes in miR-125a-5p levels and T cell subtypes. We found that miR-125a-5p levels were increased in lung tissues and serum exosomes in the silica group at 7 days and 28 days. Downregulation of miR-125a-5p attenuated α-smooth muscle actin (α-SMA), collagen I, fibronectin, p-p65, and p-inhibitor of nuclear factor kappa B (NF-κB) kinase (IKK) protein expression, while tumor necrosis factor receptor-associated factor 6 (TRAF6) and p-inhibitor of κBα (IKBα) expression were increased. MiR-125a-5p anta-miR treatment contributes to the maintenance of Th1/Th2 balance during the progression of pulmonary fibrosis. Our findings indicated that knockdown miR-125a-5p could regulate T lymphocyte subsets and significantly reduce pulmonary fibrosis by targeting TRAF6

MALAT1-miR-30c-5p-CTGF/ATG5 axis regulates silica-induced experimental silicosis by mediating EMT in alveolar epithelial cells

Epithelial-mesenchymal transdifferentiation of alveolar type Ⅱ epithelial cells is a vital source of pulmonary myofibroblasts, and myofibroblasts formation is recognized as an important phase in the pathological process of silicosis. miR-30c-5p has been determined to be relevant in the activation of the epithelial-mesenchymal transition (EMT) in numerous disease processes. However, elucidating the role played by miR-30c-5p in the silicosis-associated EMT process remains a great challenge. In this work, based on the establishment of mouse silicosis and A549 cells EMT models, miR-30c-5p was interfered with in vivo and in vitro models to reveal its effects on EMT and autophagy. Moreover, metastasis-associated lung adenocarcinoma transcript 1 (MALAT1), connective tissue growth factor (CTGF), autophagy-related gene 5 (ATG5), and autophagy were further interfered with in the A549 cells models to uncover the possible molecular mechanism through which miR-30c-5p inhibits silicosis associated EMT. The results demonstrated the targeted binding of miR-30c-5p to CTGF, ATG5, and MALAT1, and showed that miR-30c-5p could prevent EMT in lung epithelial cells by acting on CTGF and ATG5-associated autophagy, thereby inhibiting the silicosis fibrosis process. Furthermore, we also found that lncRNA MALAT1 might competitively absorb miR-30c-5p and affect the EMT of lung epithelial cells. In a word, interfering with miR-30c-5p and its related molecules (MALAT1, CTGF, and ATG5-associated autophagy) may provide a reference point for the application of silicosis intervention-related targets