title: Nrf2 links epidermal barrier function with antioxidant defense.
abstract: The skin provides an efficient permeability barrier and protects from microbial invasion and oxidative stress. Here, we show that these essential functions are linked through the Nrf2 transcription factor. To test the hypothesis that activation of Nrf2 provides skin protection under stress conditions, we determined the consequences of pharmacological or genetic activation of Nrf2 in keratinocytes. Surprisingly, mice with enhanced Nrf2 activity in keratinocytes developed epidermal thickening, hyperkeratosis and inflammation resembling lamellar ichthyosis. This resulted from upregulation of the cornified envelope proteins small proline-rich proteins (Sprr) 2d and 2h and of secretory leukocyte peptidase inhibitor (Slpi), which we identified as novel Nrf2 targets in keratinocytes. Since Sprrs are potent scavengers of reactive oxygen species and since Slpi has antimicrobial activities, their upregulation contributes to Nrf2's protective function. However, it also caused corneocyte fragility and impaired desquamation, followed by alterations in the epidermal lipid barrier, inflammation and overexpression of mitogens that induced keratinocyte hyperproliferation. These results identify an unexpected role of Nrf2 in epidermal barrier function, which needs to be considered for pharmacological use of Nrf2 activators.
authors.affiliation: Department of Biology, Institute of Cell Biology, ETH Zurich, Zurich, Switzerland. matthias.schaefer@cell.biol.ethz.ch
authors.forename: Matthias
authors.initials: M
authors.lastname: Schäfer
authors.forename: Hany
authors.initials: H
authors.lastname: Farwanah
authors.forename: Ann-Helen
authors.initials: AH
authors.lastname: Willrodt
authors.forename: Aaron J
authors.initials: AJ
authors.lastname: Huebner
authors.forename: Konrad
authors.initials: K
authors.lastname: Sandhoff
authors.forename: Dennis
authors.initials: D
authors.lastname: Roop
authors.forename: Daniel
authors.initials: D
authors.lastname: Hohl
authors.forename: Wilhelm
authors.initials: W
authors.lastname: Bloch
authors.forename: Sabine
authors.initials: S
authors.lastname: Werner
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000378:metabolism*; D005260:Female; D005786:Gene Expression Regulation; D015603:Keratinocytes / Q000276:immunology / Q000502:physiology*; D051379:Mice; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D018384:Oxidative Stress; D017382:Reactive Oxygen Species / Q000633:toxicity*; D012867:Skin / Q000276:immunology* / Q000473:pathology; D013312:Stress, Physiological
chemical_list: D000975:Antioxidants; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; D017382:Reactive Oxygen Species