title: Epidermal RAF prevents allergic skin disease.
abstract: The RAS pathway is central to epidermal homeostasis, and its activation in tumors or in Rasopathies correlates with hyperproliferation. Downstream of RAS, RAF kinases are actionable targets regulating keratinocyte turnover; however, chemical RAF inhibitors paradoxically activate the pathway, promoting epidermal proliferation. We generated mice with compound epidermis-restricted BRAF/RAF1 ablation. In these animals, transient barrier defects and production of chemokines and Th2-type cytokines by keratinocytes cause a disease akin to human atopic dermatitis, characterized by IgE responses and local and systemic inflammation. Mechanistically, BRAF and RAF1 operate independently to balance MAPK signaling: BRAF promotes ERK activation, while RAF1 dims stress kinase activation. In vivo, JNK inhibition prevents disease onset, while MEK/ERK inhibition in mice lacking epidermal RAF1 phenocopies it. These results support a primary role of keratinocytes in the pathogenesis of atopic dermatitis, and the animals lacking BRAF and RAF1 in the epidermis represent a useful model for this disease.
authors.affiliation: Department of Microbiology, Immunology and Genetics, Max F. Perutz Laboratories, University of Vienna, Vienna, Austria.
authors.forename: Josipa
authors.initials: J
authors.lastname: Raguz
authors.affiliation: Department of Microbiology, Immunology and Genetics, Max F. Perutz Laboratories, University of Vienna, Vienna, Austria.
authors.forename: Ines
authors.initials: I
authors.lastname: Jeric
authors.affiliation: Department of Microbiology, Immunology and Genetics, Max F. Perutz Laboratories, University of Vienna, Vienna, Austria.
authors.forename: Theodora
authors.initials: T
authors.lastname: Niault
authors.affiliation: Department of Microbiology, Immunology and Genetics, Max F. Perutz Laboratories, University of Vienna, Vienna, Austria.
authors.forename: Joanna Daniela
authors.initials: JD
authors.lastname: Nowacka
authors.affiliation: Department of Microbiology, Immunology and Genetics, Max F. Perutz Laboratories, University of Vienna, Vienna, Austria.
authors.forename: Sanya Eduarda
authors.initials: SE
authors.lastname: Kuzet
authors.affiliation: Department of Microbiology, Immunology and Genetics, Max F. Perutz Laboratories, University of Vienna, Vienna, Austria.
authors.forename: Christian
authors.initials: C
authors.lastname: Rupp
authors.affiliation: Department of Microbiology, Immunology and Genetics, Max F. Perutz Laboratories, University of Vienna, Vienna, Austria.
authors.forename: Irmgard
authors.initials: I
authors.lastname: Fischer
authors.affiliation: Department of Neuroscience, Istituto Di Ricerche Farmacologiche Mario Negri, Milano, Italy.|Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, Milano, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Biggi
authors.affiliation: Department of Neuroscience, Istituto Di Ricerche Farmacologiche Mario Negri, Milano, Italy.|Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, Milano, Italy.
authors.forename: Tiziana
authors.initials: T
authors.lastname: Borsello
authors.affiliation: Department of Microbiology, Immunology and Genetics, Max F. Perutz Laboratories, University of Vienna, Vienna, Austria.
authors.forename: Manuela
authors.identifier: 0000-0002-3033-391X
authors.initials: M
authors.lastname: Baccarini
mesh_terms: D000818:Animals; D003876:Dermatitis, Atopic / Q000473:pathology* / Q000517:prevention & control*; D015603:Keratinocytes / Q000502:physiology*; D051379:Mice; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics / Q000378:metabolism*; D019908:Proto-Oncogene Proteins c-raf / Q000235:genetics / Q000378:metabolism*
chemical_list: C482120:Braf protein, mouse; D048493:Proto-Oncogene Proteins B-raf; D019908:Proto-Oncogene Proteins c-raf
keywords: MAPK; RAF; allergy; atopic dermatitis; cell biology; immunology; mechanisms of disease; mouse