Open AccessNrf2 links epidermal barrier function with antioxidant defense
Author(s) -
Schäfer Matthias,
Farwanah Hany,
Willrodt AnnHelen,
Huebner Aaron J.,
Sandhoff Konrad,
Roop Dennis,
Hohl Daniel,
Bloch Wilhelm,
Werner Sabine
Publication year - 2012
Publication title -
embo molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.923
H-Index - 107
eISSN - 1757-4684
pISSN - 1757-4676
DOI - 10.1002/emmm.201200219
Subject(s) - downregulation and upregulation , keratinocyte , microbiology and biotechnology , barrier function , microphthalmia associated transcription factor , filaggrin , inflammation , slpi , desquamation , chemistry , transcription factor , reactive oxygen species , biology , immunology , biochemistry , in vitro , atopic dermatitis , medicine , pathology , gene
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.