What question did this study set out to answer?

This study aims to elucidate the role of estrogen in promoting melanogenesis via M2 macrophage polarization in melasma.

July 8, 2026International Journal of Molecular Sciences0 citationsOpen Access

Estrogen Promotes Melanogenesis Through Facilitating M2 Macrophage Skewing in Melasma

SLShen LinChina University of Mining and Technology LSLi SuBeijing Normal University - Hong Kong Baptist University United International College YDY F DengCapital University

Key Points

This study aims to elucidate the role of estrogen in promoting melanogenesis via M2 macrophage polarization in melasma.
Investigated the expression of hub genes in melasma lesions compared to perilesional skin.
Conducted in vitro and ex vivo experiments to analyze the effect of β-estradiol on M2 polarization and VEGF expression.
Assessed the signaling pathways involved in melanogenesis and M2 macrophage skewing.
Infiltration of M2 macrophages was significantly higher in melasma lesions compared to adjacent skin.
β-estradiol promoted M2 polarization, leading to increased expression of tyrosinase and melanogenesis indicators (p<0.05).
VEGF knockout or inhibition reduced the M2-driven melanogenesis, highlighting the key role of VEGF signaling.

Abstract

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.

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