AI Article Synopsis
- Atopic dermatitis (AD) is a chronic skin condition with a weakened epidermal barrier and altered immune responses, linked to reduced NRF2 activity in affected patients.
- Genetic and proteomics studies using special mouse models showed that low NRF2 levels lead to increased DNA damage and more senescent skin cells.
- While temporarily activating NRF2 may offer some protection, excessive or long-term activation can worsen skin issues, highlighting the need for careful management in treating AD patients.
Article Abstract
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.
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| http://dx.doi.org/10.1242/dmm.052126 | DOI Listing |
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