Preferential stimulation of melanocytes by M2 macrophages to produce melanin through vascular endothelial growth factor

Abstract Post-inflammatory hyperpigmentation is a skin discoloration process that occurs following an inflammatory response or wound. As the skin begins to heal, macrophages first exhibit a proinflammatory phenotype (M1) during the early stages of tissue repair and then transition to a pro-healing, anti-inflammatory phenotype (M2) in later stages. During this process, M1 macrophages remove invading bacteria and M2 macrophages remodel surrounding tissue; however, the relationship between macrophages and pigmentation is unclear. In this study, we examined the effect of macrophages on melanin pigmentation using human induced pluripotent stem cells. Functional melanocytes were differentiated from human induced pluripotent stem cells and named as hiMels. The generated hiMels were then individually cocultured with M1 and M2 macrophages. Melanin synthesis decreased in hiMels cocultured with M1 macrophages but significantly increased in hiMels cocultured with M2 macrophages. Moreover, the expression of vascular endothelial growth factor was increased in M2 cocultured media. Our findings suggest that M2 macrophages, and not M1 macrophages, induce hyperpigmentation in scarred areas of the skin during tissue repair.