Epidermal RAF prevents allergic skin disease

نویسندگان

  • Josipa Raguz
  • Ines Jeric
  • Theodora Niault
  • Joanna Daniela Nowacka
  • Sanya Eduarda Kuzet
  • Christian Rupp
  • Irmgard Fischer
  • Silvia Biggi
  • Tiziana Borsello
  • Manuela Baccarini
چکیده

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.

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عنوان ژورنال:

دوره 5  شماره 

صفحات  -

تاریخ انتشار 2016