Melanin’s Journey from Melanocytes to Keratinocytes: Uncovering the Molecular Mechanisms of Melanin Transfer and Processing

Abstract

Skin pigmentation ensures efficient photoprotection and relies on the pigment melanin, which is produced by epidermal melanocytes and transferred to surrounding keratinocytes. While the molecular mechanisms of melanin synthesis and transport in melanocytes are now well characterized, much less is known about melanin transfer and processing within keratinocytes. Over the past few decades, distinct models have been proposed to explain how melanin transfer occurs at the cellular and molecular levels. However, this remains a debated topic, as up to four different models have been proposed, with evidence presented supporting each. Here, we review the current knowledge on the regulation of melanin exocytosis, internalization, processing, and polarization. Regarding the different transfer models, we discuss how these might co-exist to regulate skin pigmentation under different conditions, i.e., constitutive and facultative skin pigmentation or physiological and pathological conditions. Moreover, we discuss recent evidence that sheds light on the regulation of melanin exocytosis by melanocytes and internalization by keratinocytes, as well as how melanin is stored within these cells in a compartment that we propose be named the melanokerasome. Finally, we review the state of the art on the molecular mechanisms that lead to melanokerasome positioning above the nuclei of keratinocytes, forming supranuclear caps that shield the nuclear DNA from UV radiation. Thus, we provide a comprehensive overview of the current knowledge on the molecular mechanisms regulating skin pigmentation, from melanin exocytosis by melanocytes and internalization by keratinocytes to processing and polarization within keratinocytes. A better knowledge of these molecular mechanisms will clarify long-lasting questions in the field that are crucial for the understanding of skin pigmentation and can shed light on fundamental aspects of organelle biology. Ultimately, this knowledge can lead to novel therapeutic strategies to treat hypo- or hyper-pigmentation disorders, which have a high socio-economic burden on patients and healthcare systems worldwide, as well as cosmetic applications.

Photoprotective melanin is maintained within keratinocytes in a storage lysosome

“…We previously proposed to name the mature melanin-containing compartment in keratinocytes melanokerasome (MKS) (Moreiras et al, 2021;. Bento-Lopes et al, 2023). After establishing that this compartment is positive for late endosomal and lysosomal markers using relatively long chase periods (up to 24 hours), we next aimed to address whether MKSs are formed by fusion with a pre-existing lysosomal compartment.…”

“…Recently, we demonstrated that melanocore internalization by keratinocytes occurs by phagocytosis, leading to the formation of a melanin-containing storage compartment, which we proposed to be named melanokerasome (MKS) (Moreiras et al, 2021;. Bento-Lopes et al, 2023). MKSs were found by us and others to be weakly acidic and weakly degradative (Correia et al, 2018; Hurbain et al, 2018).…”

Extracellular vesicles released by keratinocytes regulate melanosome maturation, melanocyte dendricity and pigment transfer

“…The ability of HEK sEVs to promote pigment transfer suggests that sEVs are crucial actors in mediating pigment exchange between these two epidermal cell types. Although the mechanisms of pigment transfer are still debated (30, 31), the generation of dendrites in HEMs is a prerequisite for the establishment of physical contacts with HEKs, while also crucial cellular structures for pigment positioning, enrichment, and transfer, further supporting that sEVs-induced HEM plasticity is pivotal to support these pigmentary functions. In agreement, maintaining the capacity of HEMs to remodel their plasma membrane and to contact HEKs is key for melanin transfer (32).…”

Phototherapy for vitiligo: A narrative review on the clinical and molecular aspects, and recent literature

“…Phototherapy affects immune cells (cytotoxic and regulatory T cells), keratinocytes, melanocytes and fibroblasts, and their function targeting both stabilization and repigmentation. 26,137,138,139,140 NBUVB led to decreased frequencies of circulating CD4+ and CD8+ central memory T cells, suggesting a potential immunosuppressive effect, while also down-regulating chemokines CXCL9 and CXCL10, which play a crucial role in the homing of memory T cells to vitiligo lesions. 141 In active NSV, patients exhibited higher levels of circulating CD4(+) CD25(high) Tregs and Foxp3(+) Tregs compared to healthy controls (studies regarding Tregs in vitiligo report variable results, especially regarding the circulating vs. skin resident cells) [142][143][144] and NB-UVB therapy decreased these levels in patients suggesting a potential impact on Tregs function.…”

“…Phototherapy affects immune cells (cytotoxic and regulatory T cells), keratinocytes, melanocytes and fibroblasts, and their function targeting both stabilization and repigmentation 26,137,138,139,140 . NBUVB led to decreased frequencies of circulating CD4+ and CD8+ central memory T cells, suggesting a potential immunosuppressive effect, while also down‐regulating chemokines CXCL9 and CXCL10, which play a crucial role in the homing of memory T cells to vitiligo lesions 141 .…”