Role of MicroRNA 146a in Regulating Regulatory T Cell Function to Ameliorate Acute Cardiac Rejection in Mice.

BACKGROUND: MiR-146a plays a critical regulatory role in the homeostasis and function of regulatory T cells (Treg cells). The purpose of this study was to investigate the role of miR-146 in regulating Treg function to ameliorate acute cardiac rejection in mice.

METHODS: We downregulated the miR-146a expression of Treg cells in recipients and constructed murine heterotopic heart transplantation models. Flow cytometry was used to analyze phenotypes of T cells. Graft rejection and cytokine changes during allograft rejection were detected. The changes of miR-146a target genes in Treg cells were detected by quantitative real-time polymerase chain reaction and western blotting.

RESULTS: Our results indicated the miR-146a antagomir increased the Treg proportion in splenocytes and blood cells in the normal immune and inflammatory conditions, but impaired the ability of Treg cells to inhibit Th1 in the inflammatory condition. During the rejection process of murine heterotopic heart transplantation, miR-146a was mainly involved in regulating Treg cells through the STAT1/IFN-γ signaling pathway and the target gene was STAT1. Reducing the miR-146a of Treg and simultaneously collaboratively applying IFN-γ neutralizing antibodies can inhibit the proliferation of CD4+ T cell, alleviate the rejection process, and promote the survival of the donor's heart.

CONCLUSION: It is possible to enhance the function of Treg cells in vivo of recipient by regulating a single miRNA, miR-146a, to achieve the purpose of inhibiting graft rejection. Collaboratively applying immunosuppressive drugs may effectively control the immune rejection and allow for the dosage and side effects of drugs to be reduced, a process that needs further study.