Immune-Cell Profiling Identifies a Defective Macrophage-Maresin 1 Resolution Axis as a Pathogenic Driver and Therapeutic Target in Vitiligo and Canities.

UNLABELLED: Impact Statement:Vitiligo and canities are pigmentary disorders caused by acquired melanocyte loss driven by oxidative stress and immune-mediated injury. We identify a defective macrophage-maresin 1 immune-resolution axis as a shared pathogenic mechanism, supporting therapeutic strategies that move beyond immune suppression toward melanocyte protection and restoration of pro-resolving macrophage function. BACKGROUND: Current models explain melanocyte loss through cytotoxic immunity, oxidative injury, intrinsic melanocyte vulnerability, and melanocyte stem-cell exhaustion; however, whether failed inflammatory resolution contributes to disease remains poorly defined. OBJECTIVE: To define the immune-cell landscape of vitiligo skin and determine whether the M2 macrophage-maresin 1 axis regulates melanocyte homeostasis. METHODS: We performed xCell transcriptome-based cellular deconvolution using full-thickness biopsies from 36 paired lesional and non-lesional vitiligo sites and 9 healthy controls. Macrophage polarization was validated by flow cytometry. Maresin 1 was evaluated in C57BL/6J spontaneous canities, tyrosinase-related protein 2 (TRP-2) immunization-induced vitiligo, and primary human melanocyte stress assays. RESULTS: Lesional vitiligo skin showed broad immune activation, including enrichment of adaptive immune cells, monocytes, macrophages, and M1 macrophages, with depletion of melanocytes and M2 macrophages. Flow cytometry confirmed reduced CD163+ M2 macrophages, increased CD80+ M1 macrophages, and a reduced M2/M1 ratio. Canities mice had reduced serum maresin 1. Exogenous maresin 1 increased skin-resident M2 macrophages, reduced M1 macrophages, decreased TRP-2-induced depigmentation, prevented canities, and enhanced melanocyte survival under growth factor deprivation and oxidative stress. CONCLUSION: Defective M2 macrophage-maresin 1 immune resolution is an unrecognized mechanism of melanocyte loss and a translational target for acquired melanocyte-loss disorders, including vitiligo, canities, and related pigmentary diseases clinically.