OP8 - The dark and the bright sides of the transcription factor Nrf2 in skin protection and disease (Nrf2 and epidermal barrier function)

Abstract

The epidermis is the outermost layer of the body. It serves as a barrier, which prevents excessive water loss and protects from environmental insults, such as UV light and air pollutants. However, these insults can damage the epidermis by formation of reactive oxygen species (ROS). A key player in the protection of cells against ROS damage is the transcription factor Nrf2, which regulates expression of various antioxidant enzymes, cytoprotective proteins and transporters. Therefore, Nrf2 is a promising pharmacological target for skin protection and cancer prevention. We analyzed the consequences of pharmacological and genetic Nrf2 activation on keratinocyte protection, barrier formation and hair follicle regeneration. Nrf2 activation protected murine keratinocytes from UVB damage through enhancement of ROS detoxification. On the other hand, strong Nrf2 activation resulted in thickening and hyperkeratosis of the interfollicular epidermis and hair follicle infundibulum as well as in inflammation. As a consequence, Nrf2 transgenic mice have scaly skin and form cysts upon ageing. 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 ROS scavengers and since Slpi has antimicrobial activities, their upregulation contributed to Nrf2’s protective function. However, it also caused corneocyte fragility and impaired desquamation, and consequently alterations in the epidermal lipid barrier, inflammation and overexpression of mitogens that induced keratinocyte hyperproliferation. Thus Nrf2 is a central regulator in protection of keratinocytes from oxidative damage but strong and prolonged Nrf2 activation leads to epidermal barrier disturbance, hyperkeratosis and cyst formation. This limits the therapeutic potential of Nrf2 activators for skin protection.