Macrophage dysregulation plays a pathogenic role in melanocyte death in mouse models of vitiligo and canities

Summary: Vitiligo and canities are caused by melanocyte death. The pathogenesis of these conditions is not clearly understood at the present. Epidemiological studies revealed a significant correlation between these two diseases, suggesting they share an overlapping pathogenic mechanism. The objective of this study is to investigate the role of innate immune cells, especially macrophages in the pathogenesis of vitiligo and canities. We employed transcriptome sequencing-based cellular deconvolution to profile the immune cells in the skin microenvironment of vitiligo patients, revealing enrichment of M1 (p=0.009) and depletion of M2 macrophages (p=0.044) in vitiligo skin. These changes were confirmed by flow cytometry. In C57BL/6J mice, maresin 1, the main functional mediator and autocrine polarization factor of M2 macrophages, not only augmented skin-resident M2 macrophages but also decreased melanocyte death after vitiligo induction using TRP2-immunization (p=0.0086). Reduced M2 macrophage function (reduced maresin 1 levels) was also observed in mice with canities (p=0.26). In addition, treatment with exogenous maresin 1 abolished spontaneous development of canities in mice (P=0.0125). Further, <i>in vitro</i> maresin 1 treatment suppressed oxidative stress-induced death of cultured melanocytes (p<0.01). In conclusion, dysregulated macrophage function contributes to melanocyte death in vitiligo and canities. Thus, treatment with maresin 1 or other M2 agonists, may be effective for the treatment and prevention of these depigmentation diseases. Ming-wan Su¹, Qianli Yang^{2, 1}, Guohong Zhang^{1, 3}, Gigi Leung¹, Ying Shi¹, Mehran Ghoreishi¹, Laura Sly⁴, Pingyu Zhou⁵, Xuejun Zhang⁶, Jinhua Xu², Youwen Zhou¹ 1. Dermatology and Skin Science, University of British Columbia, Vancouver, BC, Canada. 2. Dermatology, Huashan Hospital, Fudan University, Shanghai, Shanghai, China. 3. Pathology, Shantou University, Shantou, Guangdong, China. 4. Pediatrics, University of British Columbia, Vancouver, BC, Canada. 5. Shanghai Skin Disease Hospital, Shanghai, Shanghai, China. 6. Dermatology, Anhui Medical University, Hefei, Anhui, China. Pigmentation, Melanoma, and Melanoma Immune Surveillance