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.

A novel Nrf2-miR-29-desmocollin-2 axis regulates desmosome function in keratinocytes

“…On mating these mice with transgenic mice expressing Cre recombinase under control of a keratin 5 (K5) promoter, the STOP cassette is deleted in keratinocytes, resulting in expression of caNrf2 in all layers of the epidermis and in the hair follicles. The double mutant mice (designated K5Cre-CMVcaNrf2 mice) develop progressive epidermal thickening and hyperkeratosis as well as enlarged sebaceous glands 9,26 . However, only very minor phenotypic abnormalities are present in neonatal mice 9 .…”

“…The double mutant mice (designated K5Cre-CMVcaNrf2 mice) develop progressive epidermal thickening and hyperkeratosis as well as enlarged sebaceous glands 9,26 . However, only very minor phenotypic abnormalities are present in neonatal mice 9 . We therefore used the back skin of K5Cre-CMVcaNrf2 mice and littermate controls at P2.5 to identify direct miR targets of Nrf2 using microarray analysis (Supplementary Data 1).…”

“…3A). A comparison of the predicted targets with the mRNAs that are downregulated in the skin of K5Cre-CMVcaNrf2 mice 9 identified various desmosomal components, including Dsc2 and desmoglein 2 ( Supplementary Fig. 3B).…”

“…On the other hand, Nrf2 is activated in a variety of human cancers 6 , including cutaneous squamous cell carcinomas 7 , and activation of Nrf2 correlates with increased tumour aggressiveness 4,8 . Furthermore, we recently showed that pharmacological or genetic activation of Nrf2 in keratinocytes of mouse skin severely affects the cornified enveloping, resulting in the development of an ichthyosis-like skin disease that is characterized by acanthosis, hyperkeratosis and impaired barrier function 9 . It is therefore essential to examine the consequences of Nrf2 activation in physiological and pathological contexts and to identify the responsible Nrf2 target genes.…”

Desmosomes and Intermediate Filaments: Their Consequences for Tissue Mechanics

“…Disulfide bonding may also alter bending and buckling of keratin networks, which occur on compressive intracellular forces (Nolting et al 2014). Finally, disulfide bonds in keratins not only alter keratin organization and dynamics on mechanical signals but could tie them to the highly dynamic cellular redox network controlled by the antioxidant transcription factor Nrf2 (Schafer et al 2012).…”