Estrogen Promotes Melanogenesis Through Facilitating M2 Macrophage Skewing in Melasma

Although estrogen has been identified to play crucial roles in the development of melasma, the exact mechanism of estrogen's effect on pigmentation is incompletely elucidated. Recent studies have highlighted the pivotal role of immune cells in melasma. Interestingly, infiltrated macrophages are significantly enhanced in melasma lesions. Estrogen could facilitate M2 polarization. However, whether estrogen could stimulate melanogenesis via skewing M2 phenotype remains unknown. This study attempted to determine the significance and molecular mechanism of estrogen-induced M2 phenotype in melasma. We found that M2 infiltration was significantly increased in melasma lesions compared with perilesional skin. Arginase 1 was identified as the hub gene, and its expression was positively correlated with that of microphthalmia-associated transcription factor and tyrosinase-related protein 1 in melasma through transcriptome analysis. Moreover, β-estradiol (E2) was confirmed to promote M2 skewing while inhibiting M1 polarization via activating STAT6 signaling. Importantly, E2-induced M2 polarization robustly increased melanogenesis by increasing tyrosinase activity and expression of microphthalmia-associated transcription factor and tyrosinase in melanocytes, which were profoundly inhibited by VEGF knockdown or antagonism both in vitro and in ex vivo skin. Furthermore, VEGF was revealed to enhance melanogenesis through activating p38 MAPK and ERK1/2 signaling pathways in melanocytes. Additionally, dermal VEGF was significantly increased, and most of it colocalized with M2 macrophages in melasma lesions. Crucially, E2 administration potently reversed ovariectomy-decreased M2 skewing and subsequently promoted dermal VEGF expression and epidermal melanogenesis in the mouse tail skin, which were significantly suppressed by macrophage depletion. These findings suggest that estrogen may stimulate melanogenesis in melasma through increasing M2 skewing and VEGF expression and secretion in macrophages.