The emerging role of Nrf2 in dermatotoxicology

Abstract

The nuclear factor erythroid 2-related factor 2 (Nrf2) is best known for its role in resistance to oxidant stress. In this issue of EMBO Molecular Medicine, Nrf2-prolonged genetic activation is shown with devastating effects on skin homeostasis. The study provides novel molecular insights into poison-induced chloracne and metabolizing acquired dioxin-induced skin hamartomas or MADISH.

Figure 1

In the absence of stress, Nrf2 forms an inactive complex with Keap1, which is sequestered in the cytoplasm. Oxidative or electrophilic stress causes this complex to interact with regulatory proteins, while post-translational modifications can result in dissociation of Nrf2 from Keap1. Free Nrf2 migrates to the nucleus where it interacts with a small Maf protein to form a complex that transactivates target genes that encode antioxidant and cytoprotective proteins. In hair follicle infundibuli, Nrf2 activation stimulates Epigen, Sprr2d, and Slpi. Epgn stimulates proliferation of infundibular keratinocytes via EGFR signaling, while Sprr2d upregulation weakens the epidermal barrier. The latter leads to inflammation and enhanced keratinocyte proliferation that results in SG enlargement and acanthosis. Slpi upregulation leads to decreased desquamation, which contributes to hyperkeratosis. Nrf2 signaling is also frequently increased in cancer following events such as mutation of Nrf2 and Keap1, protein–protein interactions with Keap1, and low Keap1 expression. This increases nuclear Nrf2 levels and thus its transcriptional activity. The involvement of Epgn in cancer is not well understood. When the dioxin receptor Ahr is activated, it stimulates the expression of detoxifying genes such as Cyp1A1 and functionally interacts with Nrf2 to enhance its signaling. In MADISH, it is thought that Nrf2 and Ahr cooperate to ameliorate dioxin detoxification. AHR activates Nrf2 transcription and vice versa in other cell types.