The Therapeutic Effect of Tacrolimus in a Mouse Psoriatic Model is Associated with the Induction of Myeloid-derived Suppressor Cells

OBJECTIVES: Topical administration of Tacrolimus (TAC) is efective in the treatment of psoriasis in human patients and in mouse models. Previously, we showed that, though promoting the proliferative expansion of CD4(+)Foxp3(+) regulatory T cells (Tregs), TNFR2 was protective in mouse psoriasis model. We thus examined the role of TNFR2 signal in the efect of TAC in the treatment of mouse psoriasis. METHODS: To this end, psoriasis was induced in WT, or TNFR1 KO, or TNFR2 KO mice, and the psoriatic mice were treated with or without IMQ. RESULTS: The results showed that TAC treatment potently inhibited the development of psoriasis in WT and TNFR1 KO mice, but not in TNFR2 KO mice. However, the treatment of TAC failed to induce the expansion of Tregs in psoriatic mice. In addition to playing a decisive role in the activation of Tregs, TNFR2 stimulates the generation and activation of myeloid-derived suppressor cells (MDSCs). This led us to found that the topical treatment with TAC markedly increased the number of MDSCs in the spleen of WT and TNFR1 KO mice, but not in TNFR2 KO mice. Consequently, TAC potently decreased serum levels of IL-17A, INF-γ, and TNF and their mRNA levels in the inflamed skin lesion. CONCLUSION: Therefore, our study for the first time found that the therapeutic efect of TAC in psoriasis is associated with the expansion of MDSCs in a TNFR2-dependent manner.