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 mediates UV-induced inflammation and matrix remodeling, the role of D-DT in cutaneous photoaging remains unclear. This study investigated whether D-DT contributes to UVB-induced skin photoaging by modulating matrix metalloproteinase (MMP)-13 expression. Using D-DT knockout (Ddt^-/-) and wild-type (Ddt^+/+) mice exposed to chronic UVB, collagen degradation and immune cell infiltration were assessed. Primary dermal fibroblasts from Ddt^+/+ mice were used to examine recombinant D-DT (rD-DT)-induced MMP-13 expression and signaling pathways. UVB exposure increased D-DT expression in epidermal keratinocytes both in vivo and in vitro. Ddt^-/- mice exhibited reduced UVB-induced MMP-13 expression, preserved type I collagen levels, and diminished leukocyte and neutrophil infiltration compared 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 phosphorylation of these kinases in fibroblasts. In conclusion, UVB-induced skin photoaging is accelerated by MMP-13 expression in dermal fibroblasts following epidermal D-DT expression. These findings identified D-DT as a novel regulator of UVB-induced dermal remodeling and suggest its potential as a therapeutic target for photoaging.