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Pathogenic and therapeutic role for NRF2 signaling in ultraviolet light-induced skin pigmentation.

ABSTRACT: Mottled skin pigmentation and solar lentigines from chronic photodamage with aging involve complex interactions between keratinocytes and melanocytes. However, the precise signaling mechanisms that could serve as therapeutic targets are unclear. Herein, we report that expression of nuclear factor erythroid 2-related factor 2 (NRF2), which regulates reduction-oxidation reactions, is altered in solar lentigines and photodamaged skin. Moreover, mottled skin pigmentation in humans could be treated with topical application of the NRF2 inducer sulforaphane (SF). Similarly, UV light-induced pigmentation of WT mouse ear skin could be treated or prevented with SF treatment. Conversely, SF treatment was unable to reduce UV-induced ear skin pigmentation in mice deficient in NRF2 or in mice with keratinocyte-specific conditional deletion of IL-6R?. Taken together, NRF2 and IL-6R? signaling are involved in the pathogenesis of UV-induced skin pigmentation, and specific enhancement of NRF2 signaling could represent a potential therapeutic target.

SUBMITTER: Kerns ML

PROVIDER: S-EPMC7605539 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

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Pathogenic and therapeutic role for NRF2 signaling in ultraviolet light-induced skin pigmentation.

Kerns Michelle L ML Miller Robert J RJ Mazhar Momina M Byrd Angel S AS Archer Nathan K NK Pinkser Bret L BL Lew Lance L Dillen Carly A CA Wang Ruizhi R Miller Lloyd S LS Chien Anna L AL Kang Sewon S

JCI insight 20201015 20

Mottled skin pigmentation and solar lentigines from chronic photodamage with aging involve complex interactions between keratinocytes and melanocytes. However, the precise signaling mechanisms that could serve as therapeutic targets are unclear. Herein, we report that expression of nuclear factor erythroid 2-related factor 2 (NRF2), which regulates reduction-oxidation reactions, is altered in solar lentigines and photodamaged skin. Moreover, mottled skin pigmentation in humans could be treated w ...[more]

PMID: 33001866

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Project description:In the light of substantial discoveries in epithelial and hair pigmentation pathophysiology, this review summarizes the current understanding of skin pigmentation mechanisms. Melanocytes are pigment-producing cells, and their key regulating transcription factor is the melanocyte-specific microphthalmia-associated transcription factor (m-MITF). Ultraviolet (UV) radiation is a unique modulator of skin pigmentation influencing tanning pathways. The delayed tanning pathway occurs as UVB produces keratinocyte DNA damage, causing p53-mediated expression of the pro-opiomelanocortin (POMC) gene that is processed to release α-melanocyte-stimulating hormone (α-MSH). α-MSH stimulates the melanocortin 1 receptor (MC1R) on melanocytes, leading to m-MITF expression and melanogenesis. POMC cleavage also releases β-endorphin, which creates a neuroendocrine pathway that promotes UV-seeking behaviours. Mutations along the tanning pathway can affect pigmentation and increase the risk of skin malignancies. MC1R variants have received considerable attention, yet the allele is highly polymorphic with varied phenotypes. Vitiligo presents with depigmented skin lesions due to autoimmune destruction of melanocytes. UVB phototherapy stimulates melanocyte stem cells in the hair bulge to undergo differentiation and upwards migration resulting in perifollicular repigmentation of vitiliginous lesions, which is under sophisticated signalling control. Melanocyte stem cells, normally quiescent, undergo cyclic activation/differentiation and downward migration with the hair cycle, providing pigment to hair follicles. Physiological hair greying results from progressive loss of melanocyte stem cells and can be accelerated by acute stress-induced, sympathetic driven hyperproliferation of the melanocyte stem cells. Ultimately, by reviewing the pathways governing epithelial and follicular pigmentation, numerous areas of future research and potential points of intervention are highlighted.

Dataset Information

Pathogenic and therapeutic role for NRF2 signaling in ultraviolet light-induced skin pigmentation.

Publications

Pathogenic and therapeutic role for NRF2 signaling in ultraviolet light-induced skin pigmentation.

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