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dc.contributor.authorCandel, Sergio-
dc.contributor.authorTyrkalska, Sylwia-
dc.contributor.authorMulero, Victoriano-
dc.identifier.citationPLoS - Biology 12(05): 21001855 (2014)es_ES
dc.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.es_ES
dc.description.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 disorderses_ES
dc.description.sponsorshipThis work was supported by the Spanish Ministry of Science and Innovation (grants BIO2011-23400 and CSD2007-00002 to VM, and PhD fellowship to SC, all co-funded with Fondos Europeos de Desarrollo Regional/European Regional Development Funds), the Fundación Séneca-Murcia (grant 04538/GERM/06 to VM and PhD fellowship to RE-P), Fundação para a Ciência e Tecnologia (PhD fellowship to SdO, SFRH/BD/62674/2009), a Medical Research Council Senior Clinical fellowship to SAR (G0701932), and the European 7th Framework Initial Training Network FishForPharma (PhD fellowship to SDT, PITG-GA-2011-289209).es_ES
dc.publisherPublic Library of Sciencees_ES
dc.relation.isversionofPublisher's versiones_ES
dc.titleTnfa signaling through Tnfr2 protects skin against oxidative stress-induced inflammationes_ES
dc.description.peerreviewedPeer reviewedes_ES
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