Koch Michael, Ferrarese Luca, Ben-Yehuda Greenwald Maya, Werner Sabine
Institute of Molecular Health Sciences, Department of Biology, ETH Zürich, 8093 Zürich, Switzerland.
Dis Model Mech. 2025 Jan 1;18(1). doi: 10.1242/dmm.052126. Epub 2025 Jan 2.
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.
特应性皮炎（AD）是一种慢性炎症性皮肤病，其特征为表皮屏障受损和免疫改变。在AD患者的表皮中，细胞保护性NRF2转录因子的活性降低。为了确定这种缺陷的功能相关性，我们使用了角质形成细胞中缺乏成纤维细胞生长因子受体1和2的小鼠（K5-R1/R2小鼠），这些小鼠表现出几种类似AD的症状。对其表皮进行蛋白质组学分析发现Nrf2活性降低。这伴随着DNA损伤增加和衰老细胞数量增多。在这些小鼠的角质形成细胞中基因敲除Nrf2进一步促进了DNA损伤和衰老，但在皮肤中对Nrf2进行限时药理学激活具有轻度保护作用。令人惊讶的是，在K5-R1/R2小鼠的角质形成细胞中长期基因激活Nrf2会导致强烈的角化过度、角质形成细胞过度增殖、表皮增厚、角质形成细胞凋亡和DNA损伤增加，以及免疫细胞组成改变。这些结果揭示了Nrf2在表皮中的复杂作用，并表明有必要优化NRF2激活的持续时间和强度，以治疗AD患者的表皮改变。
