title: Tnfa signaling through tnfr2 protects skin against oxidative stress-induced inflammation.
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.
authors.affiliation: Departamento de Biología Celular e Histología, Facultad de Biología, Universidad de Murcia, Murcia, Spain; Instituto Murciano de Investigación Biosanitaria (IMIB), Murcia, Spain.
authors.forename: Sergio
authors.initials: S
authors.lastname: Candel
authors.affiliation: Departamento de Biología Celular e Histología, Facultad de Biología, Universidad de Murcia, Murcia, Spain; Instituto Murciano de Investigación Biosanitaria (IMIB), Murcia, Spain; Carlota Saldanha Lab, Instituto de Medicina Molecular, Instituto de Bioquímica, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal.
authors.forename: Sofía
authors.initials: S
authors.lastname: de Oliveira
authors.affiliation: Departamento de Biología Celular e Histología, Facultad de Biología, Universidad de Murcia, Murcia, Spain; Instituto Murciano de Investigación Biosanitaria (IMIB), Murcia, Spain.
authors.forename: Azucena
authors.initials: A
authors.lastname: López-Muñoz
authors.affiliation: Departamento de Biología Celular e Histología, Facultad de Biología, Universidad de Murcia, Murcia, Spain; Instituto Murciano de Investigación Biosanitaria (IMIB), Murcia, Spain.
authors.forename: Diana
authors.initials: D
authors.lastname: García-Moreno
authors.affiliation: Departamento de Biología Celular e Histología, Facultad de Biología, Universidad de Murcia, Murcia, Spain; Instituto Murciano de Investigación Biosanitaria (IMIB), Murcia, Spain.
authors.forename: Raquel
authors.initials: R
authors.lastname: Espín-Palazón
authors.affiliation: Departamento de Biología Celular e Histología, Facultad de Biología, Universidad de Murcia, Murcia, Spain; Instituto Murciano de Investigación Biosanitaria (IMIB), Murcia, Spain; Instituto de Investigaciones Marinas, Consejo Superior de Investigaciones Científicas (CSIC), Vigo, Spain.
authors.forename: Sylwia D
authors.initials: SD
authors.lastname: Tyrkalska
authors.affiliation: Instituto Murciano de Investigación Biosanitaria (IMIB), Murcia, Spain; Grupo de Telómeros, Envejecimiento y Cáncer, Unidad de Investigación, Departamento de Cirugía, CIBERehd. Hospital Universitario "Virgen de la Arrixaca," Murcia, Spain.
authors.forename: María L
authors.initials: ML
authors.lastname: Cayuela
authors.affiliation: MRC Centre for Developmental and Biomedical Genetics, University of Sheffield, Sheffield, United Kingdom.
authors.forename: Stephen A
authors.initials: SA
authors.lastname: Renshaw
authors.affiliation: Servicio de Dermatología, Hospital Universitario "Virgen de la Arrixaca," Murcia, Spain.
authors.forename: Raúl
authors.initials: R
authors.lastname: Corbalán-Vélez
authors.affiliation: Servicio de Anatomía Patológica, Hospital Universitario "Virgen de la Arrixaca," Murcia, Spain.
authors.forename: Inmaculada
authors.initials: I
authors.lastname: Vidal-Abarca
authors.affiliation: Institute of Molecular and Cellular Biology, National Taiwan University, Taipei, Taiwan.
authors.forename: Huai-Jen
authors.initials: HJ
authors.lastname: Tsai
authors.affiliation: Departamento de Biología Celular e Histología, Facultad de Biología, Universidad de Murcia, Murcia, Spain; Instituto Murciano de Investigación Biosanitaria (IMIB), Murcia, Spain.
authors.forename: José
authors.initials: J
authors.lastname: Meseguer
authors.affiliation: Departamento de Biología Celular e Histología, Facultad de Biología, Universidad de Murcia, Murcia, Spain; Instituto Murciano de Investigación Biosanitaria (IMIB), Murcia, Spain.
authors.forename: María P
authors.initials: MP
authors.lastname: Sepulcre
authors.affiliation: Departamento de Biología Celular e Histología, Facultad de Biología, Universidad de Murcia, Murcia, Spain; Instituto Murciano de Investigación Biosanitaria (IMIB), Murcia, Spain.
authors.forename: Victoriano
authors.initials: V
authors.lastname: Mulero
mesh_terms: D000818:Animals; D004625:Embryo, Nonmammalian; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018507:Gene Expression Regulation, Developmental; D017930:Genes, Reporter; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D015603:Keratinocytes / Q000378:metabolism / Q000473:pathology; D008010:Lichen Planus / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D019255:NADPH Oxidases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D020556:Neutrophil Infiltration; D018384:Oxidative Stress; D011565:Psoriasis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D047889:Receptors, Tumor Necrosis Factor, Type II / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D012867:Skin / Q000378:metabolism* / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism*; D015027:Zebrafish
chemical_list: D004791:Enzyme Inhibitors; D016328:NF-kappa B; D047889:Receptors, Tumor Necrosis Factor, Type II; D014409:Tumor Necrosis Factor-alpha; D049452:Green Fluorescent Proteins; D006861:Hydrogen Peroxide; D019255:NADPH Oxidases