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.
Highlights
The largest organ of the body, the skin, allows exchange with the environment while shielding the organism from insults of mechanical, chemical, and infectious nature
Downstream of the EGFR and RAS, it acts in hair follicle development and wound healing; its mild activation in Rasopathies, genetic diseases caused by activating mutations in the pathway, results in skin phenotypes ranging from thickening of palms and soles to the development of papillomas; and strong activation in keratinocytes results in tumorigenesis (Kern et al, 2011; Ratushny et al, 2012)
In line with the dermal inflammatory reaction, D/Dep2 epidermis was characterized by the robust expression of the keratinocyte activation marker K6, of the cell adhesion molecule ICAM1, and by the sporadic expression of MHC class II molecules (Figure 1E), all upregulated in inflammatory conditions including atopic dermatitis (Freedberg et al, 2001; Fan et al, 2003; Caughman et al, 1992)
Summary
The largest organ of the body, the skin, allows exchange with the environment while shielding the organism from insults of mechanical, chemical, and infectious nature. The epidermis acts as a mechanical barrier which prevents water loss and the entry of potentially harmful chemicals; in addition, through the interplay between keratinocytes in the epidermis and immune cells based mainly in the underlying dermis, the skin works as an immunological barrier actively defending the body from pathogens (Pasparakis et al, 2014; Nestle et al, 2009). Maintaining these barrier functions throughout life requires continuous regeneration of the epidermis and appropriately balanced immune responses. RAF1 ( known as CRAF) and BRAF are essential for the development and progression of RAS-induced tumors they fulfil
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