Pathogenic and therapeutic role for NRF2 signaling in ultraviolet light–induced skin pigmentation
Michelle L. Kerns, Robert J. Miller, Momina Mazhar, Angel S. Byrd, Nathan K. Archer, Bret L. Pinkser, Lance Lew, Carly A. Dillen, Ruizhi Wang, Lloyd S. Miller, Anna L. Chien, Sewon Kang
Michelle L. Kerns, Robert J. Miller, Momina Mazhar, Angel S. Byrd, Nathan K. Archer, Bret L. Pinkser, Lance Lew, Carly A. Dillen, Ruizhi Wang, Lloyd S. Miller, Anna L. Chien, Sewon Kang
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Research Article Dermatology

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-6Rα. Taken together, NRF2 and IL-6Rα signaling are involved in the pathogenesis of UV-induced skin pigmentation, and specific enhancement of NRF2 signaling could represent a potential therapeutic target.

Authors

Michelle L. Kerns, Robert J. Miller, Momina Mazhar, Angel S. Byrd, Nathan K. Archer, Bret L. Pinkser, Lance Lew, Carly A. Dillen, Ruizhi Wang, Lloyd S. Miller, Anna L. Chien, Sewon Kang

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Figure 2

NRF2 agonist treatment corresponds to an improvement in hyperpigmentation in photodamaged human skin.

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NRF2 agonist treatment corresponds to an improvement in hyperpigmentatio...
Photoprotected (upper inner arm) and photoexposed skin (forearm) either received vehicle (OIL) or sulforaphane (SF) treatment. (A) Representative indirect immunofluorescence images of NRF2 and NRF2-P expression. DAPI, nuclear staining; epi, epidermis; derm, dermis; Un, untreated. Dotted lines delineate the dermoepidermal junction. Scale bar: 50 μm. Asterisks mark areas of increased immunofluorescence signal. Arrowheads denote nuclear NRF2-P labeling. (B) Immunofluorescence signal for NRF2 and NRF2-P (mean ± SEM). (C) Representative dermoscopy images (10-fold magnification). (D) Mean mottled hyperpigmentation improvement score (scale 0–4) ± SEM. x2 (1, n = 6) = 4.3105, P = 0.037877. (E) Representative Fontana-Masson (F&M) staining. sc, stratum corneum, Scale bar: 50 μm. Black arrows indicate positive staining. (F) Quantitation of fold change in melanin per F&M staining (mean ± SEM). (G) Representative tyrosinase staining. Scale bar: 50 μm; 2-fold magnification (insets). Black arrows indicate positive staining. (H) Quantitation of fold change in tyrosinase staining (mean ± SEM). *P < 0.05, between indicated groups, as calculated by a (B) 2-tailed Student’s t test, (D) χ2 test, or (F and H) Mann Whitney U test. P values were corrected for multiple comparisons using either a 2-stage linear step-up procedure of Benjamini, Krieger, and Yekutieli (t test) or a Bonferroni correction (Mann Whitney U test).