20(S)-ginsenoside Rg3 alleviates DSS-induced colitis by promoting ERK-dependent maturation of MDSCs into M2 macrophages

Myeloid-derived suppressor cells (MDSCs) are immature myeloid cells with immunosuppressive functions that play various roles in tumors and inflammatory diseases. In colitis, MDSCs accumulate in the inflamed colon, where they mature into M2-polarized macrophages and modulate inflammatory responses. Ginsenosides, active components of ginseng, have been shown to display colitis-alleviating effects in mouse models. However, the detailed mechanisms underlying these effects are incompletely understood. This study explores the impact of ginsenosides on MDSC functions and differentiation, focusing on their potential to mitigate inflammatory symptoms in colitis. Among the 15 ginsenosides tested, Rg3(R) and Rg3(S) were found to promote the maturation of MDSCs into M2 macrophages at non-cytotoxic concentrations. This was confirmed by the increased expression of ARG1, an immunosuppressive marker. These effects were attributed to the activation of the ERK pathway, as confirmed by selective ERK inhibition. In a DSS-induced colitis mouse model, oral administration of Rg3(S) alleviated disease severity and increased MDSC differentiation into M2 macrophages in colon lamina propria, highlighting its therapeutic potential colitis.