Downregulation of exosomal miR-let-7e-5p induces macrophage M2 polarization by targeting Rictor/AKT1 signal pathway in brucellosis patients.

BACKGROUND: Numerous studies have demonstrated that exosomal microRNAs (miRNAs) are closely associated with the pathological mechanisms underlying various infectious diseases, including brucellosis. Concurrently, macrophage polarization has been identified as a critical factor in the pathogenesis of brucellosis. However, the question of whether exosomal microRNAs can regulate macrophage polarization and thereby contribute to the pathogenesis of brucellosis remains unresolved. Our study investigates the role of exosomal miR-let-7e-5p and the Rictor/AKT1 signaling pathway in macrophage polarization, elucidating a novel mechanism and potential therapeutic strategies for brucellosis. METHODS: Serum exosomes from patients with brucellosis and healthy controls were isolated and characterized. High-throughput sequencing was conducted to identify differentially expressed microRNAs. THP-1 cells were utilized for in vitro experiments. Macrophage polarization was confirmed using flow cytometry and cytometric bead array (CBA). The expression levels of miR-let-7e-5p and Rictor were quantified using quantitative reverse transcription polymerase chain reaction (qRT-PCR). Western blotting was employed to assess the protein abundance of Rictor, AKT1, and p-AKT1 (Ser473). Additionally, the relationship between miR-let-7e-5p and Rictor was explored through bioinformatics analysis, dual-luciferase reporter gene assays, and rescue experiments. RESULTS: Serum-derived exosomes from brucellosis patients induced the M2 macrophage polarization and elevated the expression of the M2 marker IL-10 in vitro. Notably, the expression of miR-let-7e-5p was found to be downregulated in the exosomes from brucellosis patients. Overexpression of miR-let-7e-5p promoted M1 macrophage polarization while inhibiting M2 polarization. Rictor was identified as a target gene of miR-let-7e-5p and is a key molecule in macrophage polarization. Furthermore, overexpression of Rictor enhanced M2 polarization and activated the AKT1 signaling pathway. The rescue experiment demonstrated that the overexpression of Rictor counteracted the effects of miR-let-7e-5p overexpression, thereby further confirming the binding relationship between these two molecules. CONCLUSIONS: The downregulation of exosomal miR-let-7e-5p promotes macrophage polarization toward the M2 phenotype through the Rictor/AKT1 signaling pathway. These findings provide insights into the pathogenesis of brucellosis and may suggest novel therapeutic strategies.