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Genetic activation of Nrf2 reduces cutaneous symptoms in a murine model of Netherton syndrome


Muzumdar, Sukalp; Koch, Michael; Hiebert, Hayley; Bapst, Andreas; Gravina, Alessia; Bloch, Wilhelm; Beer, Hans-Dietmar; Werner, Sabine; Schäfer, Matthias (2020). Genetic activation of Nrf2 reduces cutaneous symptoms in a murine model of Netherton syndrome. Disease Models & Mechanisms, 13(5):dmm042648.

Abstract

Netherton syndrome is a monogenic autosomal recessive disorder primarily characterized by the detachment of the uppermost layer of the epidermis, the stratum corneum. It results from mutations in the SPINK5 gene, which codes for a kallikrein inhibitor. Uncontrolled kallikrein activity leads to premature desquamation, resulting in a severe epidermal barrier defect and subsequent life-threatening systemic infections and chronic cutaneous inflammation. Here, we show that genetic activation of the transcription factor nuclear factor (erythroid-derived 2)-like 2 (Nfe2l2/Nrf2) in keratinocytes of Spink5 knockout mice, a model for Netherton syndrome, significantly alleviates their cutaneous phenotype. Nrf2 activation promoted attachment of the stratum corneum and concomitant epidermal barrier function, and reduced the expression of pro-inflammatory cytokines such as tumor necrosis factor α and thymic stromal lymphopoietin. Mechanistically, we show that Nrf2 activation induces overexpression of secretory leukocyte protease inhibitor (Slpi), a known inhibitor of kallikrein 7 and elastase 2, in mouse and human keratinocytes in vivo and in vitro, respectively. In the Spink5-deficient epidermis, the upregulation of Slpi is likely to promote stabilization of corneodesmosomes, thereby preventing premature desquamation. Our results suggest pharmacological NRF2 activation as a promising treatment modality for Netherton syndrome patients.

Abstract

Netherton syndrome is a monogenic autosomal recessive disorder primarily characterized by the detachment of the uppermost layer of the epidermis, the stratum corneum. It results from mutations in the SPINK5 gene, which codes for a kallikrein inhibitor. Uncontrolled kallikrein activity leads to premature desquamation, resulting in a severe epidermal barrier defect and subsequent life-threatening systemic infections and chronic cutaneous inflammation. Here, we show that genetic activation of the transcription factor nuclear factor (erythroid-derived 2)-like 2 (Nfe2l2/Nrf2) in keratinocytes of Spink5 knockout mice, a model for Netherton syndrome, significantly alleviates their cutaneous phenotype. Nrf2 activation promoted attachment of the stratum corneum and concomitant epidermal barrier function, and reduced the expression of pro-inflammatory cytokines such as tumor necrosis factor α and thymic stromal lymphopoietin. Mechanistically, we show that Nrf2 activation induces overexpression of secretory leukocyte protease inhibitor (Slpi), a known inhibitor of kallikrein 7 and elastase 2, in mouse and human keratinocytes in vivo and in vitro, respectively. In the Spink5-deficient epidermis, the upregulation of Slpi is likely to promote stabilization of corneodesmosomes, thereby preventing premature desquamation. Our results suggest pharmacological NRF2 activation as a promising treatment modality for Netherton syndrome patients.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > University Hospital Zurich > Dermatology Clinic
Dewey Decimal Classification:610 Medicine & health
Scopus Subject Areas:Life Sciences > Neuroscience (miscellaneous)
Health Sciences > Medicine (miscellaneous)
Life Sciences > Immunology and Microbiology (miscellaneous)
Life Sciences > General Biochemistry, Genetics and Molecular Biology
Uncontrolled Keywords:Immunology and Microbiology (miscellaneous) , General Biochemistry, Genetics and Molecular Biology, Medicine (miscellaneous), Neuroscience (miscellaneous)
Language:English
Date:1 May 2020
Deposited On:16 Jun 2020 11:50
Last Modified:01 Aug 2020 18:49
Publisher:The Company of Biologists Ltd.
ISSN:1754-8403
OA Status:Gold
Free access at:PubMed ID. An embargo period may apply.
Publisher DOI:https://doi.org/10.1242/dmm.042648
PubMed ID:32457102
Project Information:
  • : FunderSNSF
  • : Grant ID31003A_169204
  • : Project TitleRole of cytokines and environmental cues in wound repair and inflammatory skin disease

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