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Quantitative Proteomics Identifies Reduced NRF2 Activity and Mitochondrial Dysfunction in Atopic Dermatitis

Koch, Michael; Kockmann, Tobias; Rodriguez, Elke; Wehkamp, Ulrike; Hiebert, Paul; Ben-Yehuda Greenwald, Maya; Stölzl, Dora; Beer, Hans Dietmar; Tschachler, Erwin; Weidinger, Stephan; Werner, Sabine; auf dem Keller, Ulrich

Authors

Michael Koch

Tobias Kockmann

Elke Rodriguez

Ulrike Wehkamp

Maya Ben-Yehuda Greenwald

Dora Stölzl

Hans Dietmar Beer

Erwin Tschachler

Stephan Weidinger

Sabine Werner

Ulrich auf dem Keller



Abstract

Atopic dermatitis is the most common inflammatory skin disease and is characterized by a deficient epidermal barrier and cutaneous inflammation. Genetic studies suggest a key role of keratinocytes in atopic dermatitis pathogenesis, but the alterations in the proteome that occur in the full epidermis have not been defined. Using a pressure-cycling technology and data-independent acquisition approach, we performed quantitative proteomics of epidermis from healthy volunteers and lesional and nonlesional patient skin. Results were validated by targeted proteomics using parallel reaction monitoring mass spectrometry and immunofluorescence staining. Proteins that were differentially abundant in the epidermis of patients with atopic dermatitis versus in healthy control reflect the strong inflammation in lesional skin and the defect in keratinocyte differentiation and epidermal stratification that already characterizes nonlesional skin. Most importantly, they reveal impaired activation of the NRF2-antioxidant pathway and reduced abundance of mitochondrial proteins involved in key metabolic pathways in the affected epidermis. Analysis of primary human keratinocytes with small interfering RNA‒mediated NRF2 knockdown revealed that the impaired NRF2 activation and mitochondrial abnormalities are partially interlinked. These results provide insight into the molecular alterations in the epidermis of patients with atopic dermatitis and identify potential targets for pharmaceutical intervention.

Citation

Koch, M., Kockmann, T., Rodriguez, E., Wehkamp, U., Hiebert, P., Ben-Yehuda Greenwald, M., …auf dem Keller, U. (2023). Quantitative Proteomics Identifies Reduced NRF2 Activity and Mitochondrial Dysfunction in Atopic Dermatitis. Journal of Investigative Dermatology, 143(2), 220-231.e7. https://doi.org/10.1016/j.jid.2022.08.048

Journal Article Type Article
Acceptance Date Aug 25, 2022
Online Publication Date Sep 13, 2022
Publication Date Feb 1, 2023
Deposit Date Feb 20, 2024
Publicly Available Date Feb 20, 2024
Journal Journal of Investigative Dermatology
Print ISSN 0022-202x
Electronic ISSN 1523-1747
Publisher Elsevier
Peer Reviewed Peer Reviewed
Volume 143
Issue 2
Pages 220-231.e7
DOI https://doi.org/10.1016/j.jid.2022.08.048
Public URL https://hull-repository.worktribe.com/output/4553981

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Publisher Licence URL
https://creativecommons.org/licenses/by-nc-nd/4.0/

Copyright Statement
© 2022 The Authors. Published by Elsevier, Inc. on behalf of the Society for Investigative Dermatology. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).




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