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.