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Title

Tnfa signaling through Tnfr2 protects skin against oxidative stress-induced inflammation

AuthorsCandel, Sergio; Tyrkalska, Sylwia; Mulero, Victoriano
Issue Date2014
PublisherPublic Library of Science
CitationPLoS - Biology 12(05): 21001855 (2014)
AbstractTNFα 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
Description14 páginas, 8 figuras.-- Sergio 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.
Publisher version (URL)http://dx.doi.org/10.1371/journal.pbio.1001855
URIhttp://hdl.handle.net/10261/98318
DOI10.1371/journal.pbio.1001855
ISSN1544-9173
E-ISSN1545-7885
Appears in Collections:(IIM) Artículos
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