Elevated miR-155 expression induces immunosuppression via CD39(+) regulatory T-cells in sepsis patient

Abstract

Background: An altered microRNA profile exists in many infectious diseases, including sepsis. CD39(+) regulatory T-cells (Tregs) have a remarkable immunosuppressive effect and play an important role in the regulation of immune balance in sepsis. However, the correlation between microRNA changes and the ratio of CD39(+) Tregs in sepsis patients has not yet been reported. The altered microRNA expression profile in sepsis patients was analyzed in this study. Moreover, the correlation between microRNAs and disease severity and prognosis was investigated. Furthermore, the correlation between microRNAs and the percentage of peripheral blood CD39(+) Tregs was investigated and further verified in an animal model.

Methods: Sixty sepsis patients and 30 healthy controls were included. The difference in microRNA expression was investigated by microRNA microarray and was further confirmed by real-time quantitative PCR. The correlations between microRNA changes and the Sepsis-related Organ Failure Assessment (SOFA) score, severity of sepsis, and survival were analyzed. The percentage CD39(+) Tregs in the peripheral blood of sepsis patients was measured by flow cytometry. The correlation between microRNAs and the percentage CD39(+) Tregs was analyzed and further confirmed in a mouse sepsis model.

Results: Compared to healthy controls, sepsis patients exhibited a significantly elevated microRNA-155 (miR-155) level (p < 0.05), which was positively related to a higher SOFA score (r = 0.641, p < 0.05) and a greater severity of sepsis. The area under the receiver operating characteristic curve of miR-155 used for the prediction of 28-day survival was 0.763, with a cut-off point of 2.47. Patients with a miR-155 level >2.47 had a lower 28-day survival (p < 0.05). The miR-155 level of patients was proportional to the percentage of CD39(+) Tregs (r = 0.637, p < 0.05). After transfection with miR-155 inhibitor, the ratio of CD39(+) Tregs in mice with sepsis was significantly reduced (p < 0.05).

Conclusions: A higher level of miR-155 indicated a more severe condition and poorer prognosis in sepsis patients. The possible underlying mechanism could be that miR-155 induces an increased percentage of CD39(+) Tregs and thus immunosuppression.

Keywords: MicroRNA; MicroRNA microarray; Outcome; Regulatory T-cell; Sepsis.