The functional role of Wnt5a in keratinocytes in psoriasis vulgaris

Psoriasis vulgaris ist eine komplexe, entzündliche Hauterkrankung, die sowohl durch veränderte Differenzierung und Proliferation von Keratinozyten, als auch durch Aktivierung von Immunzellen gekennzeichnet ist. Obwohl verschiedene Regionen im menschlichen Genom mit der Krankheit assoziiert werden, müssen die genauen genetischen Variationen, die zur Psoriasisentstehung führen, noch identifiziert werden. Neben genetischer Prädisposition fördern bestimmte Umweltfaktoren das Auftreten psoriatischer Plaques. Außer den bekannten Triggerfaktoren wie Stress, viralen Infekten oder Lithium scheinen auch das Signalmolekül Wnt5a und Interferonalpha eine wichtige Rolle zu spielen. Die im Folgenden dargestellten Ergebnisse konnten die bereits bekannte Überexpression von Wnt5a in psoriatischer Haut bestätigen. Das Signalmolekül wurde in der Basalzellschicht der Epidermis von Psoriasispatienten lokalisiert. Die Hochregulation von Wnt5a in Keratinozyten steigerte deren Sensitivität gegenüber Interferon-alpha, außerdem induzierte Wnt5a Interferon-abhängige Zielgene wie IFI27 und IFI78. Ein Synergismus zwischen Wnt5a- und Interferon- alpha- Signaltransduktion ließ sich am Beispiel von APP und Nedd8 nachweisen. APP ist durch seine Wirkung über sAPP-alpha als bedeutender epidermaler Wachstumsfaktor besonders hinsichtlich neuer Therapieansätze bei der Psoriasis interessant. Die beschriebenen Beobachtungen und Zusammenhänge verdeutlichen, welch bedeutende funktionelle Rolle das Signalmolekül Wnt5a bei der Psoriasis vulgaris spielt.Psoriasis vulgaris is a complex inflammatory skin disorder involving both altered differentiation and proliferation in keratinocytes, as well as activation of immune cells. Although several genomic regions have been shown to be associated with the disease, the precise genetic variations regulating susceptibility to psoriasis have yet to be defined. Besides genetic susceptibility, environmental triggers drive disease flares. Well known factors are stress response, viral infections or lithium. Beyond these, the differentiation factor Wnt5a and interferon-alpha seem to play a prominent role during psoriasis pathogenesis. The following results show an overexpression of Wnt5a in psoriatic skin and its localisation in the basal cell layer of the epidermis. The upregulation of Wnt5a in keratinocytes increased their sensitivity against interferon-alpha. Furthermore Wnt5a induced interferon target genes like IFI27 and IFI78. A synergism between Wnt5a and interferon-alpha signal transduction was shown for APP and Nedd8. APP signalling through sAPP-alpha which is an important epidermal growth factor, is especially interesting in terms of new therapy approaches in psoriasis. The activation of a Wnt-interferon signalling network occurs uniformally in psoriasis and appears to be a converging point downstream of distinct genetic susceptibility subgroups

Wnt5a Exhibits Layer-Specific Expression in Adult Skin, Is Upregulated in Psoriasis, and Synergizes with Type 1 Interferon

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.We 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 IFNalpha/Wnt5a induction.The 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

PPAR delta enhances keratinocyte proliferation in psoriasis and induces heparin-binding EGF-like growth factor

Psoriasis is a common skin disease involving keratinocyte proliferation and altered differentiation, as well as T-cell activation. Here, we show that altered gene transcription in psoriatic skin lesions is highly reproducible between independent data sets. Analysis of gene expression confirmed dysregulation in all expected functional categories, such as IFN signaling and keratinocyte differentiation, and allowed molecular fingerprinting of a previously characterized dendritic cell subset associated with psoriasis tumor necrosis factor alpha (TNF-α)- and inducible nitric oxide synthase (iNOS)-producing CD11bINT DC (Tip-DC). Unexpectedly, a large group of dysregulated transcripts was related to fatty acid signaling and adipocyte differentiation, exhibiting a pattern consistent with the activation of peroxisome proliferator-activated receptorδ (PPARδ). PPARδ itself was strongly induced in psoriasis in vivo. In primary keratinocytes, PPARδ was induced by the transcription factor activator protein 1, in particular by junB, but not by canonical WNT signaling, in contrast to its regulation in colon carcinoma cells. Activation of PPARδ enhanced proliferation of keratinocytes, while this was inhibited by knockdown of PPARδ. Finally, heparin-binding EGF-like growth factor (HB-EGF), known to induce epidermal hyperplasia and itself overexpressed in psoriasis, was identified as a direct target gene of PPARδ. The present data suggest that activation of PPARδ is a major event in psoriasis, contributing to the hyperproliferative phenotype by induction of HB-EGF