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.
Highlights
Reactive oxygen species (ROS) are highly aggressive molecules that are produced in various cellular reactions, for example in the respiratory chain
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
We previously reported on the characterization of this mutant and generation of mice expressing constitutively active Nrf2 mutant (caNrf2) under control of a b-actin promoter (Schafer et al, 2010) using a construct containing the caNrf2 cDNA preceded by a floxed stop cassette
Summary
Reactive oxygen species (ROS) are highly aggressive molecules that are produced in various cellular reactions, for example in the respiratory chain. As a result of these studies several patents for the use of Nrf activators as skin protecting agents were filed, for example for sulforaphane [publication number KR20080045083 (A)] or oltipraz [publication number KR20020075954 (A)]. While limited activation of these mechanisms is beneficial, prolonged activation of Nrf in the epidermis caused corneocyte fragility and impaired desquamation, resulting in the development of an ichthyosis-like skin disease. These findings unravelled an unexpected role of Nrf in skin homeostasis and disease that goes well beyond its wellcharacterized antioxidant function
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