MicroRNA-218 alleviates sepsis inflammation by negatively regulating VOPP1 via JAK/STAT pathway

OBJECTIVE: To investigate the possible role of microRNA-218 in the pathogenesis of sepsis and its underlying mechanism.

PATIENTS AND METHODS: MicroRNA-218 expression in peripheral blood mononuclear cells (PBMCs) of 53 sepsis patients and 20 healthy controls was detected by quantitative Real-Time Polymerase Chain Reaction (qRT-PCR). MicroRNA-218 expression in Treg cells of sepsis patients and healthy controls was also detected. The binding condition of microRNA-218 to VOPP1 was confirmed by dual-luciferase reporter gene assay and RNA binding protein immunoprecipitation (RIP) assay, respectively. Furthermore, sepsis mouse model was constructed. MicroRNA-218 mimics or inhibitor was injected into mouse tail vein, respectively. The proportion of Treg cells was compared between sepsis mice injected with microRNA-218 mimics and inhibitor. Expressions of microRNA-218 and VOPP1 in Treg cells extracted from sepsis mouse were detected. ELISA (enzyme-linked immunosorbent assay) assay was conducted to detect serum levels of inflammatory factors (TNF-α, IL-6, TGF-β, and IL-10) in sepsis mouse. Finally, protein expressions of key genes in JAK/STAT pathway in sepsis mouse spleen were detected by Western blot.

RESULTS: MicroRNA-218 expression in sepsis patients was remarkably lower than that of healthy controls, which was gradually decreased with the deteriorating symptoms. Specifically, microRNA-218 expression was the lowest in patients who died of sepsis. Downregulated microRNA-218 was seen in Treg cells extracted from advanced sepsis patients. Both dual-luciferase reporter gene assay and RIP assay suggested that microRNA-218 can bind to VOPP1. VOPP1 expression was negatively regulated by microRNA-218. In advanced sepsis mouse, administration of microRNA-218 mimics increased expressions of TNF-α and IL-6, but decreased expressions of IL-10 and TGF-β. Western blot results indicated that microRNA-218 can inhibit the JAK/STAT pathway in sepsis mice.

CONCLUSIONS: MicroRNA-218 expression in the PBMCs of sepsis patients was remarkably reduced, which inhibited sepsis development via negatively regulating VOPP1 and suppressing JAK/STAT pathway.

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