α-Mangostin Inhibited M1 Polarization of Macrophages/Monocytes in Antigen-Induced Arthritis Mice by Up-Regulating Silent Information Regulator 1 and Peroxisome Proliferators-Activated Receptor γ Simultaneously

Background: alpha-Mangostin (MG) showed the potentials in alleviating experimental arthritis, inhibiting inflammatory polarization of macrophages/monocytes, and regulating peroxisome proliferators-activated receptor gamma (PPAR-gamma) and silent information regulator 1 (SIRT1) signals. The aim of this study was to analyze the correlations among the above-mentioned properties.Methods: Antigen-induced arthritis (AIA) was established in mouse, which was treated with MG in combination with SIRT1/PPAR-gamma inhibitors to clarify the role of the two signals in the anti-arthritic actions. Pathological changes were systematically investigated. Phenotypes of cells were investigated by flow cytometry. Expression and co-localization of SIRT1 and PPAR-gamma proteins in joint tissues were observed by the immunofluorescence method. Finally, clinical implications from the synchronous up-regulation of SIRT1 and PPAR-gamma were validated by experiments in vitro.Results: SIRT1 and PPAR-gamma inhibitors (nicotinamide and T0070097) reduced the therapeutic effects of MG on AIA mice, and abrogated MG-induced up-regulation of SIRT1/PPAR-gamma and inhibition of M1 polarization in macrophages/monocytes. MG has a good binding affinity to PPAR-gamma, and MG promoted the co-expression of SIRT1 and PPAR-gamma in joints. Synchronously activating SIRT1 and PPAR-gamma was revealed to be necessary by MG to repress inflammatory responses in THP-1 monocytes.Conclusion: MG binds PPAR-gamma and excites this signaling to initiate ligand-dependent anti-inflammatory activity. Due to certain unspecified signal transduction crosstalk mechanism, it then promoted SIRT1 expression and further limited inflammatory polarization of macrophages/monocytes in AIA mice.

Automated summary

This study found that alpha-Mangostin (MG) can alleviate experimental arthritis, inhibit inflammatory polarization of macrophages/monocytes, and regulate PPAR-gamma and SIRT1 signals. The results showed that MG activates SIRT1 expression by binding PPAR-gamma, thereby suppressing inflammatory responses.