Activation of Nrf2 in keratinocytes causes chloracne (MADISH)-like skin disease in mice (original) (raw)
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The emerging role of Nrf2 in dermatotoxicology
EMBO Molecular Medicine, 2014
The nuclear factor erythroid 2‐related factor 2 (Nrf2) is best known for its role in resistance to oxidant stress. In this issue of EMBO Molecular Medicine, Nrf2‐prolonged genetic activation is shown with devastating effects on skin homeostasis. The study provides novel molecular insights into poison‐induced chloracne and metabolizing acquired dioxin‐induced skin hamartomas or MADISH.
Nrf2 Involvement in Chemical-Induced Skin Innate Immunity
Frontiers in Immunology, 2019
Exposure to certain chemicals disturbs skin homeostasis. In particular, protein-reactive chemical contact sensitizers trigger an inflammatory immune response resulting in eczema and allergic contact dermatitis. Chemical sensitizers activate innate immune cells which orchestrate the skin immune response. This involves oxidative and inflammatory pathways. In parallel, the Nrf2/Keap1 pathway, a major ubiquitous regulator of cellular oxidative and electrophilic stress is activated in the different skin innate immune cells including epidermal Langerhans cells and dermal dendritic cells, but also in keratinocytes. In this context, Nrf2 shows a strong protective capacity through the downregulation of both the oxidative stress and inflammatory pathways. In this review we highlight the important role of Nrf2 in the control of the innate immune response of the skin to chemical sensitizers.
Nrf2 links epidermal barrier function with antioxidant defense
EMBO Molecular Medicine, 2012
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.
Alternatives to Laboratory Animals
The 21st century paradigm for toxicology and the adverse outcome pathway concept envisage a future toxicology largely based on mechanistic in vitro assays and relying mainly on cellular models. In the skin sensitisation field, this concept was not intuitive at the beginning. Given the high structural diversity of skin sensitising molecules, classical receptor binding as the molecular initiating event in a cell-based assay could be excluded from the start, leaving the question of how cells could sense potential skin sensitising chemicals and be able to differentiate them from non-sensitisers. When we entered this field in 2006, we realised that, in another emerging field of toxicology, detailed work on the antioxidant/electrophile sensing pathway Keap1/Nrf2/ARE was being performed. We postulated that, based on their intrinsic electrophilicity, a large structural variety of skin sensitisers would activate this pathway. This was demonstrated in a preliminary pilot study with an existin...
Toxicology in Vitro, 2013
a b s t r a c t 31 The KeratinoSens™ assay is an in vitro screen for the skin sensitization potential of chemicals. It is based 32 on a luciferase reporter gene under the control of the antioxidant response element of the aldoketoreduc-33 tase gene AKR1C2. The transferability, reproducibility, and predictivity of the KeratinoSens™ assay have 34 been investigated in detail and it is currently under assessment at the European Center for Validation of 35 Alternatives to animal testing (ECVAM). Here we investigate the sensitizer-induced gene expression in 36 the KeratinoSens™ cell line at the mRNA level and discriminate Nrf2-dependent and Nrf2-independent 37 events by using siRNA to better characterize this test system at the molecular level. The results show that 38 (i) the sensitizer-induced luciferase signal in KeratinoSens™ cells is completely dependent on Nrf2. The 39 same holds true for the luciferase induction observed for the false positive chemical Tween80, indicating 40 that the false positive result is not due to recruitment of an alternative transcription factor. (ii) Luciferase 41 induction parallels the induction of endogenous Nrf2-dependent genes, indicating that the luciferase 42 signal is representative for the sensitizer-induced Nrf2-response. (iii) The induction by sensitizers of 43 additional genetic markers related to heat shock proteins and cellular stress could be reproduced in 44 the KeratinoSens™ cell line and they were shown to be Nrf2-independent. These results confirm that 45 the KeratinoSens™ cell line is a rapid and adequate screening tool to assess the sensitizer-induced 46 Nrf2-response in keratinocytes.