NRF2 in the Epidermal Pigmentary System

Abstract

Melanogenesis is a major part of the environmental responses and tissue development of the integumentary system. The balance between reduction and oxidation (redox) governs pigmentary responses, for which coordination among epidermal resident cells is indispensable. Here, we review the current understanding of melanocyte biology with a particular focus on the "master regulator" of oxidative stress responses (i.e., the Kelch-like erythroid cell-derived protein with cap'n'collar homology-associated protein 1-nuclear factor erythroid-2-related factor 2 system) and the autoimmune pigment disorder vitiligo. Our investigation revealed that the former is essential in pigmentogenesis, whereas the latter results from unbalanced redox homeostasis and/or defective intercellular communication in the interfollicular epidermis (IFE). Finally, we propose a model in which keratinocytes provide a "niche" for differentiated melanocytes and may "imprint" IFE pigmentation.

Keywords: NRF2; antioxidant; melanocyte; oxidative stress; reactive oxygen species; redox; vitiligo.

Figure 1

Overview of melanogenesis pathways. Tyrosinase (TYR), the rate-limiting enzyme for melanogenesis, oxidizes tyrosine to L-3,4-dihydroxyphenylalanine (L-DOPA) and dopaquinone. Dopaquinone reacts with excess cysteine/glutathione and generates cysteinyldopa, giving rise to pheomelanin. With cystine/glutathione disulfide abundance, dopaquinone generates dopachrome. Dopachrome undergoes spontaneous decarboxylation and forms 5,6-dihydroxyindole (DHI). In the presence of tyrosinase-related protein 2 (TYRP2), dopachrome produces 5,6-dihydroxyindole-2-carboxylic acid (DHICA) through tautomerization. TYR and tyrosinase-related protein 1 (TYRP1) catalyze further conversions, yielding eumelanin. The catalytic activity of TYR or TYRP1 generates superoxide anions (O₂⁻) and hydrogen peroxide (H₂O₂).

Figure 2

Summary of thiols/disulfides in the epidermal pigmentary system. Interfollicular epidermis (IFE) pigmentation largely depends on the balance between reduction and oxidation (redox) status with internal or external causes. The former refers to mitochondria-derived reactive oxygen species (ROS) during melanogenesis, and the latter may correspond to epidermal differentiation in which keratinocyte (KC) structural proteins undergo extensive disulfide bridge formation upon the initiation of cornification (transition from the stratum granulosum [SG] to the stratum corneum [SC]). Successful cornification largely depends on the biochemical nature of the structural protein loricrin (LOR, indicated as granules). Differentiating layer (stratum spinosum [SS] and SG)-specific desmosomal cadherin desmoglein 1 (DSG1) appears indispensable for functional IFE pigmentogenesis: melanosome transfer and maturation (eumelanogenesis) (left). In vitiligo melanocytes, stress from environmental factors (e.g., toxic chemicals) can cause aberrations in the IFE antioxidant systems in genetically predisposed individuals. Breached immune tolerance recruits melanocyte antigen-specific CD8⁺ cytotoxic T cells (CTLs) expressing CXC receptor type 3 (CXCR3) or CD49⁺ resident memory T cells (TRMs) in vitiligo (right), whereas the autoreactive CTLs constitutively become anergic with the help of regulatory T cells (Tregs) in homeostasis (left). The homeostatic gradient of nuclear factor erythroid-2-related factor 2 (NRF2)-mediated epidermal antioxidative defense and ensuing cornification yield a polymerized/pigmented SC, protecting against oxidative damage. However, local clonal expansion of CTLs in the IFE eventually eliminates melanocytes from the IFE niche (the epidermal melanin unit), perturbing the xenobiotic metabolism coordinated by NRF2 and resulting in depigmentation (leukoderma).