Tnfa signaling through tnfr2 protects skin against oxidative stress-induced inflammation

Candel, S., de Oliveira, S., López-Muñoz, A., García-Moreno, D., Espín-Palazón, R., Tyrkalska, S.D., Cayuela, M.L., Renshaw, S.A., Corbalán-Vélez, R., Vidal-Abarca, I., Tsai, H.J., Meseguer, J., Sepulcre, M.P., Mulero, V.
PLoS Biology   12: e1001855 (Journal)
Registered Authors
de Oliveira, Sofia, Mulero, Victor, Renshaw, Steve A., Tsai, Huai-Jen
Larvae, Neutrophils, Keratinocytes, Zebrafish, Psoriasis, Embryos, Inflammatory bowel disease, Inflammation
MeSH Terms
  • Animals
  • Embryo, Nonmammalian
  • Enzyme Inhibitors/pharmacology
  • Gene Expression Regulation, Developmental
  • Genes, Reporter
  • Green Fluorescent Proteins/genetics
  • Green Fluorescent Proteins/metabolism
  • Humans
  • Hydrogen Peroxide/metabolism
  • Keratinocytes/metabolism
  • Keratinocytes/pathology
  • Lichen Planus/genetics
  • Lichen Planus/metabolism*
  • Lichen Planus/pathology
  • NADPH Oxidases/antagonists & inhibitors
  • NADPH Oxidases/genetics
  • NADPH Oxidases/metabolism*
  • NF-kappa B/genetics
  • NF-kappa B/metabolism
  • Neutrophil Infiltration
  • Oxidative Stress
  • Psoriasis/genetics
  • Psoriasis/metabolism*
  • Psoriasis/pathology
  • Receptors, Tumor Necrosis Factor, Type II/genetics
  • Receptors, Tumor Necrosis Factor, Type II/metabolism*
  • Signal Transduction
  • Skin/metabolism*
  • Skin/pathology
  • Tumor Necrosis Factor-alpha/genetics
  • Tumor Necrosis Factor-alpha/metabolism*
  • Zebrafish
24802997 Full text @ PLoS Biol.
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.
Genes / Markers
Mutation and Transgenics
Human Disease / Model Data
Sequence Targeting Reagents
Engineered Foreign Genes
Errata and Notes