Wnt5a Exhibits Layer-Specific Expression in Adult Skin,Is Upregulated in Psoriasis,and Synergizes with Type 1 Interferon |
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| Authors: | Malgorzata Romanowska Alan Evans David Kellock Susan E Bray Kathleen McLean Susanne Donandt John Foerster |
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| Institution: | 1. Division of Experimental Medicine, University of Dundee, Dundee, Scotland, United Kingdom.; 2. Tayside Tissue Bank, University of Dundee, Dundee, Scotland, United Kingdom.; 3. Department of Dermatology, University of Dundee, Dundee, Scotland, United Kingdom.; 4. Charité Medical University, Berlin, Germany.;Tulane National Primate Research Center, United States of America |
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| Abstract: | BackgroundWnt5a is a member of the wingless-type patterning regulators important in pre-natal development. The expression and distribution of Wnt5a and its receptors frizzled (fzd) 3 and fzd 5 in adult human skin have not been comprehensively studied to date.Methodology/Principal FindingsWe here show that Wnt5a, fzd3, fzd5, as well as fzd6 are restricted to specific layers in normal epidermis, analogous to their zonal distribution in hair follicles, suggesting a role in adult skin differentiation. In line, Wnt5a and fzd5 are both overexpressed and re-distributed in the epidermis of psoriasis which involves disturbed keratinocyte differentiation. Functionally, Wnt5a lowers the concentration of IFN required to induce target genes, and increases the magnitude of IFN target gene induction, suggesting a molecular mechanism underlying IFN hypersensitivity in psoriasis. Finally, we identify nedd8 and the amyloid precursor APP, previously shown to be upregulated in psoriasis, as targets of synergistic IFNα/Wnt5a induction.Conclusions/SignificanceThe present data (i) suggest that Wnt5a regulates epidermal differentiation even in adult skin and (ii) identify synergistic induction of type 1 IFN target genes as a novel mode of Wnt5a action. Targeting Wnt5a in the skin may reduce IFN hypersensitivity and be of therapeutical value. |
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