Sergio Candel 1 , 2 , Sofía de Oliveira 1 , 2 , 3 , Azucena López-Muñoz 1 , 2 , Diana García-Moreno 1 , 2 , Raquel Espín-Palazón 1 , 2 , Sylwia D. Tyrkalska 1 , 2 , 4 , María L. Cayuela 2 , 5 , Stephen A. Renshaw 6 , Raúl Corbalán-Vélez 7 , Inmaculada Vidal-Abarca 8 , Huai-Jen Tsai 9 , José Meseguer 1 , 2 , María P. Sepulcre 1 , 2 , Victoriano Mulero 1 , 2 , *
6 May 2014
A new zebrafish model of skin inflammatory disease explains new-onset and worsening psoriasis and lichen planus in patients receiving anti-TNFα therapy.
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 2O 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 2O 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.
Psoriasis and lichen planus are chronic, debilitating skin diseases that affect millions of people worldwide. TNFα is a multifunctional cytokine that mediates acute and chronic inflammation. While TNFα antagonist therapy is used for autoimmune or chronic inflammatory diseases, such as inflammatory bowel disease (IBD), numerous studies have reported new-onset psoriasis and lichen planus following such therapy. We have used the unique advantages of the zebrafish embryo to identify a novel phenotype that mirrors this unexplained and paradoxical onset of psoriasis and lichen planus. We found that depletion of Tnfa or its receptor Tnfr2 caused skin inflammation and hyperproliferation of keratinocytes through the activation of a Duox1/H 2O 2/NF-κB positive feedback inflammatory loop. Strikingly, DUOX1 was drastically induced in the skin lesions of psoriasis and lichen planus patients, and pharmacological inhibition of Duox1 abrogated skin inflammation, placing Duox1-derived H 2O 2 upstream of this inflammatory loop. Our results suggest that therapies targeting DUOX1 and H 2O 2 could provide innovative approaches to the management of skin inflammatory disorders.