Tnfa signaling through tnfr2 protects skin against oxidative stress-induced inflammation.
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, w...
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| Main Authors: | , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2014-05-01
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| Series: | PLoS Biology |
| Online Access: | https://doi.org/10.1371/journal.pbio.1001855 |
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| author | Sergio Candel Sofía de Oliveira Azucena López-Muñoz Diana García-Moreno Raquel Espín-Palazón Sylwia D Tyrkalska María L Cayuela Stephen A Renshaw Raúl Corbalán-Vélez Inmaculada Vidal-Abarca Huai-Jen Tsai José Meseguer María P Sepulcre Victoriano Mulero |
| author_facet | Sergio Candel Sofía de Oliveira Azucena López-Muñoz Diana García-Moreno Raquel Espín-Palazón Sylwia D Tyrkalska María L Cayuela Stephen A Renshaw Raúl Corbalán-Vélez Inmaculada Vidal-Abarca Huai-Jen Tsai José Meseguer María P Sepulcre Victoriano Mulero |
| author_sort | Sergio Candel |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-eff14dad52ab4e5ea1a64dd68ff5a645 |
| institution | Kabale University |
| issn | 1544-9173 1545-7885 |
| language | English |
| publishDate | 2014-05-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Biology |
| spelling | doaj-art-eff14dad52ab4e5ea1a64dd68ff5a6452025-08-20T03:46:12ZengPublic Library of Science (PLoS)PLoS Biology1544-91731545-78852014-05-01125e100185510.1371/journal.pbio.1001855Tnfa signaling through tnfr2 protects skin against oxidative stress-induced inflammation.Sergio CandelSofía de OliveiraAzucena López-MuñozDiana García-MorenoRaquel Espín-PalazónSylwia D TyrkalskaMaría L CayuelaStephen A RenshawRaúl Corbalán-VélezInmaculada Vidal-AbarcaHuai-Jen TsaiJosé MeseguerMaría P SepulcreVictoriano MuleroTNFα 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.https://doi.org/10.1371/journal.pbio.1001855 |
| spellingShingle | Sergio Candel Sofía de Oliveira Azucena López-Muñoz Diana García-Moreno Raquel Espín-Palazón Sylwia D Tyrkalska María L Cayuela Stephen A Renshaw Raúl Corbalán-Vélez Inmaculada Vidal-Abarca Huai-Jen Tsai José Meseguer María P Sepulcre Victoriano Mulero Tnfa signaling through tnfr2 protects skin against oxidative stress-induced inflammation. PLoS Biology |
| title | Tnfa signaling through tnfr2 protects skin against oxidative stress-induced inflammation. |
| title_full | Tnfa signaling through tnfr2 protects skin against oxidative stress-induced inflammation. |
| title_fullStr | Tnfa signaling through tnfr2 protects skin against oxidative stress-induced inflammation. |
| title_full_unstemmed | Tnfa signaling through tnfr2 protects skin against oxidative stress-induced inflammation. |
| title_short | Tnfa signaling through tnfr2 protects skin against oxidative stress-induced inflammation. |
| title_sort | tnfa signaling through tnfr2 protects skin against oxidative stress induced inflammation |
| url | https://doi.org/10.1371/journal.pbio.1001855 |
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