Cargando…
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...
Autores principales: | , , , , , , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2014
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4011677/ https://www.ncbi.nlm.nih.gov/pubmed/24802997 http://dx.doi.org/10.1371/journal.pbio.1001855 |
_version_ | 1782314821421629440 |
---|---|
author | Candel, Sergio de Oliveira, Sofía López-Muñoz, Azucena García-Moreno, Diana Espín-Palazón, Raquel Tyrkalska, Sylwia D. Cayuela, María L. Renshaw, Stephen A. Corbalán-Vélez, Raúl Vidal-Abarca, Inmaculada Tsai, Huai-Jen Meseguer, José Sepulcre, María P. Mulero, Victoriano |
author_facet | Candel, Sergio de Oliveira, Sofía López-Muñoz, Azucena García-Moreno, Diana Espín-Palazón, Raquel Tyrkalska, Sylwia D. Cayuela, María L. Renshaw, Stephen A. Corbalán-Vélez, Raúl Vidal-Abarca, Inmaculada Tsai, Huai-Jen Meseguer, José Sepulcre, María P. Mulero, Victoriano |
author_sort | Candel, Sergio |
collection | PubMed |
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 H(2)O(2) 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 H(2)O(2) 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 | Online Article Text |
id | pubmed-4011677 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2014 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-40116772014-05-09 Tnfa Signaling Through Tnfr2 Protects Skin Against Oxidative Stress–Induced Inflammation Candel, Sergio de Oliveira, Sofía López-Muñoz, Azucena García-Moreno, Diana Espín-Palazón, Raquel Tyrkalska, Sylwia D. Cayuela, María L. Renshaw, Stephen A. Corbalán-Vélez, Raúl Vidal-Abarca, Inmaculada Tsai, Huai-Jen Meseguer, José Sepulcre, María P. Mulero, Victoriano PLoS Biol Research Article 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 H(2)O(2) 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 H(2)O(2) 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. Public Library of Science 2014-05-06 /pmc/articles/PMC4011677/ /pubmed/24802997 http://dx.doi.org/10.1371/journal.pbio.1001855 Text en © 2014 Candel et al http://creativecommons.org/licenses/by/4.0/ 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 properly credited. |
spellingShingle | Research Article Candel, Sergio de Oliveira, Sofía López-Muñoz, Azucena García-Moreno, Diana Espín-Palazón, Raquel Tyrkalska, Sylwia D. Cayuela, María L. Renshaw, Stephen A. Corbalán-Vélez, Raúl Vidal-Abarca, Inmaculada Tsai, Huai-Jen Meseguer, José Sepulcre, María P. Mulero, Victoriano Tnfa Signaling Through Tnfr2 Protects Skin Against Oxidative Stress–Induced Inflammation |
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 |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4011677/ https://www.ncbi.nlm.nih.gov/pubmed/24802997 http://dx.doi.org/10.1371/journal.pbio.1001855 |
work_keys_str_mv | AT candelsergio tnfasignalingthroughtnfr2protectsskinagainstoxidativestressinducedinflammation AT deoliveirasofia tnfasignalingthroughtnfr2protectsskinagainstoxidativestressinducedinflammation AT lopezmunozazucena tnfasignalingthroughtnfr2protectsskinagainstoxidativestressinducedinflammation AT garciamorenodiana tnfasignalingthroughtnfr2protectsskinagainstoxidativestressinducedinflammation AT espinpalazonraquel tnfasignalingthroughtnfr2protectsskinagainstoxidativestressinducedinflammation AT tyrkalskasylwiad tnfasignalingthroughtnfr2protectsskinagainstoxidativestressinducedinflammation AT cayuelamarial tnfasignalingthroughtnfr2protectsskinagainstoxidativestressinducedinflammation AT renshawstephena tnfasignalingthroughtnfr2protectsskinagainstoxidativestressinducedinflammation AT corbalanvelezraul tnfasignalingthroughtnfr2protectsskinagainstoxidativestressinducedinflammation AT vidalabarcainmaculada tnfasignalingthroughtnfr2protectsskinagainstoxidativestressinducedinflammation AT tsaihuaijen tnfasignalingthroughtnfr2protectsskinagainstoxidativestressinducedinflammation AT meseguerjose tnfasignalingthroughtnfr2protectsskinagainstoxidativestressinducedinflammation AT sepulcremariap tnfasignalingthroughtnfr2protectsskinagainstoxidativestressinducedinflammation AT mulerovictoriano tnfasignalingthroughtnfr2protectsskinagainstoxidativestressinducedinflammation |