D-Dopachrome Tautomerase Facilitates UVB-Induced Skin Photoaging in Mice.

D-dopachrome tautomerase [D-DT; or macrophage migration inhibitory factor (MIF)-2] is a homolog of MIF, which shares receptor usage and downstream signaling. Although MIF is known to mediate UV-induced inflammation and matrix remodeling, the role of D-DT in cutaneous photoaging remains unclear. Therefore, this study investigated whether D-DT contributes to UVB-induced skin photoaging by modulating the expression of matrix metalloproteinase (MMP)-13. Using D-DT knockout (Ddt-/-) and wild-type (Ddt+/+) mice exposed to chronic UVB, this study assessed collagen degradation and immune cell infiltration in the skin. Also, primary dermal fibroblasts from Ddt+/+ mice were used to examine the recombinant D-DT (rD-DT)-induced MMP-13 expression and the signaling pathways. UVB exposure markedly increased the D-DT expression in epidermal keratinocytes both in vivo and in vitro. In addition to attenuated skin inflammation, Ddt-/- mice exhibited reduced UVB-induced MMP-13 expression levels, preserved type I collagen levels, and diminished leukocyte and neutrophil infiltration, comparing with wild-type mice. rD-DT directly up-regulated MMP-13 in fibroblasts, and this effect was suppressed by extracellular signal-regulated kinase and c-Jun N-terminal kinase inhibitors. Furthermore, rD-DT induced the phosphorylation of extracellular signal-regulated kinase and c-Jun N-terminal kinase in fibroblasts. In conclusion, UVB-induced skin photoaging is accelerated by the expression of MMP-13 in dermal fibroblasts following the epidermal expression of D-DT. These findings identified D-DT as a novel regulator of UVB-induced dermal remodeling and suggest its potential as a therapeutic target for photoaging.