PORTEFEUILLE

The skin serves as a protective barrier, which prevents water loss and penetration of allergens, irritants and pathogens into the body. A disturbance of the epidermal barrier is involved in the pathogenesis of a variety of major skin diseases, including Ichthyosis, Psoriasis and Atopic Dermatitis. In recent years the analysis of the pathomechanisms underlying these diseases, including barrier function and immunological alterations, resulted in the development of novel and effective therapies.

Much less attention is paid to rare skin diseases with epidermal barrier defects. One of the most severe rare diseases is Netherton Syndrome, with a prevalence of 1.35 per 100.000. In Netherton Syndrome patients, mutations in the so-called Spink5 gene lead to overactivation of proteases, which are responsible for epidermal desquamation. The consequence is the detachment of the most upper layers of the epidermis, which constitute a major part of the epidermal barrier. This leads to an epidermal barrier break-down, which then allows the penetration of allergens, irritants and/or pathogens. This and other mechanisms stimulate inflammation and allergic reactions, which can be life threatening for Netherton Syndrome patients.

In this project we have genetically activated the transcription factor Nrf2 in a mouse model for Netherton Syndrome. This resulted in a partial rescue of the epidermal phenotype due to attenuation of the epidermal barrier defect and a reduced inflammatory response. The consequence of Nrf2 activation by pharmacological substances is currently under investigation. Our analyses provide the basis for the development of a novel therapy for Netherton Syndrome.

Current therapeutic strategies to re-establish a functional barrier in Netherton Syndrome patients are rather inefficient and unspecific. Therefore, there is a strong need for development of improved and targeted therapies.

Previous findings from our lab and others suggest that activation of Nrf2 could be a powerful strategy to reduce barrier function impairments resulting from different epidermal abnormalities. In this project we found that activation of Nrf2 induces compensatory pathways that partially restore the epidermal barrier function in a mouse model of Netherton Syndrome. This provides a rational for a future clinical trial to determine the usefulness of topical application of pharmacological NRF2 activators in Netherton Syndrome patients. This seems feasible, since NRF2-activating compounds are in clinical trials for prevention of other diseases.

We have analyzed the consequences of genetic activation of Nrf2 in mice with a mutation in the Spink5 gene. These mice display a detachment of the upper layer of the epidermis leading to a severe barrier disturbance and consequently water loss and skin inflammation. This resembles the clinical symptoms of Netherton Syndrome patients.

Genetic activation of Nrf2 in these mice resulted in a partial rescue of the epidermal phenotype characterized by reduced water loss and downregulation of inflammation markers. This was due to stabilization of the epidermis and thus reduced detachment of the most upper layers. Experiments to test the effect of NRF2-activating compounds on barrier function in vitro and in vivo are currently ongoing.

Hovnanian, A. 2013. Netherton syndrome: skin inflammation and allergy by loss of protease inhibition. Cell Tissue Res. 351:289-300;
Huebner, A.J., Dai, D., Morasso, M., Schmidt, E.E., Schafer, M., Werner, S., and Roop, D.R. 2012. Amniotic fluid activates the nrf2/keap1 pathway to repair an epidermal barrier defect in utero. Dev Cell 23:1238-1246;
Schäfer, M., Dutsch, S., auf dem Keller, U., Navid, F., Schwarz, A., Johnson, D.A., Johnson, J.A., and Werner, S. 2010. Nrf2 establishes a glutathione-mediated gradient of UVB cytoprotection in the epidermis. Genes & Dev 24:1045-1058;
Schäfer, M., Farwanah, H., Willrodt, A.H., Huebner, A.J., Sandhoff, K., Roop, D., Hohl, D., Bloch, W., and Werner, S. 2012. Nrf2 links epidermal barrier function with antioxidant defense. EMBO Mol Med 4:364-379.

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