Abstract
Author SummaryPsoriasis 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/H2O2/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 H2O2 upstream of this inflammatory loop. Our results suggest that therapies targeting DUOX1 and H2O2 could provide innovative approaches to the management of skin inflammatory disorders.
Highlights
Tumor necrosis factor a (TNFa) is a multifunctional cytokine that mediates key roles in acute and chronic inflammation, antitumor responses, and infection
We found that depletion of Tnfa or its receptor Tnfr2 caused skin inflammation and hyperproliferation of keratinocytes through the activation of a dual oxidase 1 (Duox1)/H2O2/NF-kB positive feedback inflammatory loop
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 H2O2 upstream of this inflammatory loop
Summary
Tumor necrosis factor a (TNFa) is a multifunctional cytokine that mediates key roles in acute and chronic inflammation, antitumor responses, and infection. Numerous studies have reported new-onset psoriasis and lichen planus, or worsening of existing psoriasis, following TNFa antagonist therapy in adult patients [5,6,7,8,9,10]. Despite these clinical data pointing to an ambiguous function of TNFa in psoriasis and lichen planus, the role of TNFa, and in particular the contribution of each TNFR, in the regulation of skin inflammation has been scarcely studied. Mice with an arrested canonical NF-kB activation pathway in the keratinocytes develop a severe
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