Dose-dependent effects of Nrf2 on the epidermis in chronic skin inflammation

Atopic dermatitis (AD) is a chronic inflammatory skin disease, characterized by an impaired epidermal barrier and immunological alterations. The activity of the cytoprotective NRF2 transcription factor is reduced in the epidermis of AD patients. To determine the functional relevance of this deficiency, we used mice lacking fibroblast growth factor receptors 1 and 2 in keratinocytes (K5-R1/R2 mice), which exhibit several AD-like symptoms. Proteomics analysis of their epidermis revealed reduced Nrf2 activity. This was accompanied by an increase in DNA damage and in the number of senescent cells. Genetic deletion of Nrf2 in keratinocytes of these mice further promoted DNA damage and senescence, but time-limited pharmacological activation of Nrf2 in the skin had a mild protective effect. Surprisingly, long-term genetic activation of Nrf2 in keratinocytes of K5-R1/R2 mice caused strong hyperkeratosis, keratinocyte hyperproliferation, epidermal thickening, increased keratinocyte apoptosis and DNA damage, and altered immune cell composition. These results reveal a complex role of Nrf2 in the epidermis and show the necessity to optimize the duration and intensity of NRF2 activation for the treatment of epidermal alterations in patients with AD.