Axl Involved in Mineral Trioxide Aggregate Induces Macrophage Polarization

Introduction: In this study, we examined the effect of mineral trioxide aggregate (MTA) on macrophage polarization and the potential involvement of Axl/nuclear factor kappa B (NF-kappa B) signaling in mediating the effect of MTA. Methods: The human monocyte cell line THP-1 was cultured with MTA solution for 1, 2, or 3 days, and the population change of M2 macrophages was analyzed by flow cytometry. Expression of M2 cytokines was examined by enzyme-linked immunosorbent assay. Phagocytosis and angiogenesis-induction ability were also assayed. The involvement of Axl/NF-kappa B signaling in MTA-treated cells was examined by analyzing phosphorylation status of Axl, Akt, IKK alpha/beta, and I kappa B alpha. Specific inhibitors for Axl/Akt/NF-kappa B signaling were added to MTA-treated THP-1 cells, and their cytokine expression change was examined. Results: Flow cytometry analysis showed that MTA treatment increased CD206 + cells in a time-dependent way. After MTA treatment, the expression of M2-related cytokines was up regulated. MTA also enhanced phagocytic ability and the ability of THP-1 cells to induce angiogenesis. Treatment of MTA led to activate Axl/Akt/NF-kappa B signal axis by phosphorylation of Axl, Akt, IKK alpha/beta/, I kappa B alpha, and p65. In addition, MTA-induced interleukin 10, transforming growth factor beta, and vascular endothelial growth factor expression was suppressed as specific inhibitors were added. Conclusions: Our findings indicate that MTA is able to induce macrophage polarization toward the M2 phenotype, with up-regulation of interleukin 10, transforming growth factor beta, and vascular endothelial growth factor, and that Axl/Akt/NF-kappa B signaling participates in this process. These results provide the cellular and molecular basis of MTA's anti-inflammatory action in clinical applications.