Tnfa Signaling Through Tnfr2 Protects Skin Against Oxidative Stress-Induced Inflammation

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

Research output: Contribution to journalArticlepeer-review

34 Scopus citations

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.

Original languageEnglish (US)
Article numbere1001855
JournalPLoS biology
Volume12
Issue number5
DOIs
StatePublished - 2014

ASJC Scopus subject areas

  • Neuroscience(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)
  • Agricultural and Biological Sciences(all)

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