Candel, S., de Oliveira, S., Lopez-Munoz, A. et al. (11 more authors) (2014) Tnfa Signaling Through Tnfr2 Protects Skin Against Oxidative Stress-Induced Inflammation. PLoS Biology, 12 (5). ISSN 1545-7885
Abstract
TNFα overexpression has been associated with several chronic inflammatory diseases, including psoriasis, lichen planus, rheumatoid arthritis, and inflammatory bowel disease. Paradoxically, numerous studies have reported new-onset psoriasis and lichen planus following TNFα antagonist therapy. Here, we show that genetic inhibition of Tnfa and Tnfr2 in zebrafish results in the mobilization of neutrophils to the skin. Using combinations of fluorescent reporter transgenes, fluorescence microscopy, and flow cytometry, we identified the local production of dual oxidase 1 (Duox1)-derived H2O2 by Tnfa- and Tnfr2-deficient keratinocytes as a trigger for the activation of the master inflammation transcription factor NF-κB, which then promotes the induction of genes encoding pro-inflammatory molecules. In addition, pharmacological inhibition of Duox1 completely abrogated skin inflammation, placing Duox1-derived H2O2 upstream of this positive feedback inflammatory loop. Strikingly, DUOX1 was drastically induced in the skin lesions of psoriasis and lichen planus patients. These results reveal a crucial role for TNFα/TNFR2 axis in the protection of the skin against DUOX1-mediated oxidative stress and could establish new therapeutic targets for skin inflammatory disorders.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © 2014 Candel et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
Dates: |
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Institution: | The University of Sheffield |
Academic Units: | The University of Sheffield > Faculty of Medicine, Dentistry and Health (Sheffield) > Department of Infection and Immunity (Sheffield) |
Depositing User: | Symplectic Sheffield |
Date Deposited: | 17 Nov 2014 10:18 |
Last Modified: | 17 Nov 2014 10:18 |
Published Version: | http://dx.doi.org/10.1371/journal.pbio.1001855 |
Status: | Published |
Publisher: | Public Library Science |
Refereed: | Yes |
Identification Number: | 10.1371/journal.pbio.1001855 |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:81541 |