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

UNLABELLEDImpact 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.

BACKGROUNDCurrent 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.

OBJECTIVETo define the immune-cell landscape of vitiligo skin and determine whether the M2 macrophage-maresin 1 axis regulates melanocyte homeostasis.

METHODSWe 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.

RESULTSLesional 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.

CONCLUSIONDefective 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.

Abstract from PubMed