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

D-dopachrome tautomerase (D-DT, or MIF-2) is a homolog of the macrophage migration inhibitory factor (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, we investigated whether D-DT contributes to UVB-induced skin photoaging by modulating the expression of MMP-13. Using D-DT knockout (Ddt-/-) and wild-type (Ddt+/+) mice exposed to chronic UVB, we assessed collagen degradation and immune cell infiltration in the skin. We also used primary dermal fibroblasts from Ddt+/+ mice 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 WT mice. rD-DT directly upregulated MMP-13 in fibroblasts, and this effect was suppressed by ERK and JNK inhibitors. Furthermore, rD-DT induced the phosphorylation of ERK and JNK 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.