Increased splicing of CXCR3 isoform B (CXCR3B) by impaired NRF2 signaling leads to melanocyte apoptosis in active vitiligo.

Apoptotic melanocytes (MCs) may release neoantigenic epitopes preceding epidermal infiltration by autoreactive CD8 T cells in early vitiligo. However, the mechanism by which vitiligo MCs are prone to apoptosis under oxidative stress remains elusive. Pro-apoptotic receptor C-X-C motif chemokine receptor 3 isoform B (CXCR3B) is critical for inducing MC apoptosis in the inflammatory microenvironment of lesional vitiligo skin. Here, we show that C-X-C motif chemokine ligand 10 (CXCL10), a functional ligand for CXCR3B, is upregulated in primary dermal fibroblasts and in CD90 reticular fibroblasts of vitiligo skin. The number of CXCR3B MCs was increased in active vitiligo skin compared with healthy skin and stable vitiligo skin. Mechanistically, impaired nuclear factor erythroid 2-related factor 2 (NRF2) signaling in oxidatively stressed MCs leads to the elevated expression of CXCR3B and increased apoptosis. The overexpression of NRF2 prevents MCs from CXCL10-induced apoptosis through upregulation of pro-survival receptor CXCR3 isoform A (CXCR3A). Overall, MCs expressing CXCR3B are more susceptible to apoptosis. Suppressing CXCR3B could be a promising therapeutic approach to extinguish inflammation in vitiligo skin.