Exosomal miRNA let-7i-5p alleviates asthma triggered by RSV-induced exosomes by regulating dendritic cell autophagy...

Asthma is a chronic airway inflammatory disease, with respiratory syncytial virus (RSV) infection being a significant trigger. Studies have demonstrated the potential therapeutic effects of exosomes derived from bone marrow mesenchymal stem cells (BMSCs) on asthma. However, our preliminary research revealed that exosomes from BMSCs induced by RSV (Exos-RSV) can induce asthma, and among the exosomes, the miRNA let-7i-5p exhibits low expression. The role of miRNA let-7i-5p in asthma mediated by Exos-RSV remains to be further elucidated.

In order to elucidate the role of miRNA let-7i-5p in Exos-RSV induced asthma, based on previous research, we obtained Exos-RSV with different miRNA let-7i-5p contents through plasmid transfection technology, and used these Exos-RSV to intervene in mice and dendritic cells (DCs) to construct animal and cell models for comparison. ELISA was used to evaluate changes in inflammatory factors in animal serum. Histological staining was used to evaluate lung tissue lesions. CCK-8 was used to evaluate cell viability, and flow cytometry was used to evaluate cell cycle and apoptosis. RT-qPCR and western blotting was used to evaluate the expression of autophagy and related molecules in animal lung tissue and DCs in vitro.

We observed that when Exos-RSV lacked miRNA let-7i-5p, asthmatic mice exhibited elevated serum levels of IL-5, IL-13, and IL-33, along with pulmonary tissue infiltration of inflammatory cells, goblet cell hyperplasia, increased collagen deposition, and enhanced expression of ET-1, collagen1, and Fibronectin proteins. Conversely, overexpression of miRNA let-7i-5p in exosomes alleviated these manifestations. In vitro experiments showed that Exos-RSV, which were deficient in miRNA let-7i-5p, increased the proportions of both early and late apoptotic DCs, elevated G1-phase cell ratios, and reduced S-phase cell proportions. When exosomes overexpressed miRNA let-7i-5p, the number of early apoptotic DCs decreased, while cell proportions across phases remained stable. Mechanistic studies revealed that Exos-RSV lacking miRNA let-7i-5p enhanced DCs autophagy and inhibited the MITF/DAP1/P70S6K signaling pathway in both in vivo and in vitro models. Conversely, overexpression of miRNA let-7i-5p partially reversed these changes.

The lack of miRNA let-7i-5p in Exos-RSV is a key mechanism underlying asthma induction. Exosomal miRNA let-7i-5p acts as an autophagy inhibitor by targeting and regulating autophagy-related signaling pathways, thereby alleviating airway inflammation and remodeling in asthma, providing a promising therapeutic strategy.