Evidence for Altered Wnt Signaling in Psoriatic Skin

Abstract

The Wnt gene family encodes a set of highly conserved secreted signaling proteins that have major roles in embryogenesis and tissue homeostasis. Yet the expression of this family of important mediators in psoriasis, a disease characterized by marked changes in keratinocyte growth and differentiation, is incompletely understood. We subjected 58 paired biopsies from lesional and uninvolved psoriatic skin and 64 biopsies from normal skin to global gene expression profiling. WNT5A transcripts were up-regulated 5-fold in lesional skin, accompanied by increased Wnt-5a protein levels. Notably, WNT5A mRNA was markedly induced by IL-1α, TNF-α, IFN-γ and TGF-α in cultured keratinocytes. FZD2 and FZD5, which encode receptors for Wnt5A, were also increased in lesional psoriatic skin. In contrast, expression of WIF1 mRNA, encoding a secreted antagonist of the Wnt proteins, was down-regulated >10-fold in lesional skin, along with decreased WIF-1 immunostaining. Interestingly, pathway analysis along with reduced AXIN2 expression and lack of nuclear translocation of beta-catenin indicated a suppression of canonical Wnt signaling in lesional skin. Our results suggest a shift away from canonical Wnt signaling towards non-canonical pathways driven by interactions between Wnt-5a and its cognate receptors in psoriasis, accompanied by impaired homeostatic inhibition of Wnt signaling by WIF-1 and Dkk.

Epigenetic Downregulation of SFRP4 Contributes to Epidermal Hyperplasia in Psoriasis

“…Several studies reported that the global Wnt signaling pathway or expression of some specific Wnt proteins was altered in psoriasis patients (8,10,42,43). In fact, a gene-expression study of 58 patients with psoriasis and 64 normal healthy controls by microarray showed that WIF1 was the most strongly downregulated gene in psoriatic skin versus normal skin (44).…”

“…More microarrays demonstrated that Wnt5a was increased in psoriatic plaques of patients, indicating that the noncanonical Wnt signaling pathway might be activated in psoriasis (8,43). Despite the controversial findings of whether the canonical or noncanonical Wnt pathway was activated in psoriasis (9,10,42), all of the studies pointed out that the expression of inhibitory factors related to Wnt signaling, such as SFRP, Dkk, and WIF, were reduced to some extent in psoriasis (8,10). In the current study, we found that the expression of SFRP4, a negative modulator of Wnt signaling (45), was decreased in lesional skin of psoriasis mouse models and patients.…”

“…Geneticassociated studies identified dozens of psoriasis-associated genes and the signaling pathways (3), such as the IL-23/Th17 axis (4), the NF-kB signaling pathway (5), and the epidermal differentiation complex (6,7). Recently, several independent array-based studies revealed that Wnt signaling was altered in psoriatic skin compared with normal skin (8)(9)(10), suggesting that this pathway might be involved in psoriasis pathogenesis.…”

“…SFRPs are expressed in a variety of embryonic and adult tissues, indicating that they may provide a common mechanism for inhibiting Wnt signaling in diverse tissues and cell types (16). Despite the intensive studies of Wnt proteins in controlling cell proliferation and differentiation, very little is known about the functions of such Wnt modulator molecules in epidermal hyperplasia in psoriasis (10).…”

Recombinant Wnt3a and Wnt5a elicit macrophage cytokine production and tolerization to microbial stimulation via Toll‐like receptor 4

“…The 19 mammalian homologues have distinct expression patterns in embryonic and adult tissues and their during infections with mycobacteria, Gram-negative and Grampositive bacteria [2][3][4][5][6], and chronic inflammation in rheumatoid arthritis, atherosclerosis, obesity, and psoriasis [7][8][9][10][11][12].…”