Data di Pubblicazione:
2016
Citazione:
Epidermal RAF prevents allergic skin disease / J. Raguz, I. Jeric, T. Niault, J.D. Nowacka, S.E. Kuzet, C. Rupp, I. Fischer, S. Biggi, T. Borsello, M. Baccarini. - In: ELIFE. - ISSN 2050-084X. - 5(2016 Jul), pp. e14012.1-e14012.23. [10.7554/eLife.14012]
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.
Tipologia IRIS:
01 - Articolo su periodico
Keywords:
thymic stromal lymphopoietin; atopic-dermatitis; T-cell; B-raf; tight junctions; messenger-RNA; inflammation; expression; cancer; mice
Elenco autori:
J. Raguz, I. Jeric, T. Niault, J.D. Nowacka, S.E. Kuzet, C. Rupp, I. Fischer, S. Biggi, T. Borsello, M. Baccarini
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