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.
Highlights
We here show that Wnt5a and its putative receptor Fzd5 are overexpressed in psoriasis, that Wnt5a increases the sensitivity of keratinocytes towards type 1 interferon, and that nedd8 and APP are synergistically induced by Wnt5a and IFNa
The unexpected finding that Wnt5a and fzd3, fzd5, and fzd6 proteins are highly compartmentalized in normal adult human epidermis, reminiscent of the distribution of wnt signalling components in the hair follicle, raises the question of the role of this system in the dynamics of keratinocyte turnover in the skin
WNT5a induces IL12 [6], which is central to psoriasis, as indicated by the therapeutic efficacy of antibodies targeted at IL12p40 and by the genetic association of IL12 with psoriasis [24,25]
Summary
Wnt5a represents the prototypical so-called non-canonical Wnt family members which signal not by inducing, or may even inhibit, the transcriptional activation of b-catenin. Apart from its complex role in development, Wnt5a is expressed in various adult tissues. Among its diverse biological activities, Wnt5a promotes proliferation in endothelial cells and glioblastoma cells [1,2,3], as well as adhesion in fibroblasts and breast cancer cells [4,5]. Wnt5a is upregulated in synovial fibroblasts of inflammatory joints in rheumatoid arthritis where it induces IL6, IL8, and IL15 [8]. Wnt5a 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
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