Epigenetic Downregulation of SFRP4 Contributes to Epidermal Hyperplasia in Psoriasis

Abstract

Psoriasis is a chronic recurrent inflammatory skin disorder characterized by the dysregulated cross-talk between epidermal keratinocytes and immune cells, leading to keratinocyte hyperproliferation. Several studies demonstrated that Wnt pathway genes were differentially expressed in psoriatic plaques and likely were involved in the pathophysiology of disease. However, the molecular mechanisms underlying Wnt signaling regulation in epidermal hyperplasia in psoriasis remain largely unknown. We report that the expression of secreted frizzled-related protein (SFRP) 4, a negative regulator of the Wnt signaling pathway, was diminished in lesional skin of mouse models and patients with psoriasis. SFRP4 directly inhibited excessive keratinocyte proliferation evoked by proinflammatory cytokines in vitro. Pharmacological inhibition of Wnt signaling or intradermal injection of SFRP4 decreased the severity of the psoriasiform skin phenotype in vivo, including decreased acanthosis and reduced leukocyte infiltration. Mechanistically, we identified that aberrant promoter methylation resulted in epigenetic downregulation of SFRP4 in inflamed skin of patients with psoriasis and in the IL-23–induced mouse model. Our findings suggest that this epigenetic event is critically involved in the pathogenesis of psoriasis, and the downregulation of SFRP4 by CpG island methylation is one possible mechanism contributing to the hyperplasia of epidermis in the disease.

645 Imiquimod has strain-dependent effects in mice and does not uniquely model human psoriasis

“…Fold changes (IMQ/CTL) estimated by RNA-seq were usually correlated with those from previous microarray studies [2,[20][21][22], but the strength of such correlations varied by strain and among array experiments (Additional file 7a-d). Correspondence was weaker relative to one microarray study utilizing ear skin, rather than back skin, suggesting that site of application is influential (Additional file 7b).…”

“…Additional datasets incorporated into analyses include those from prior microarray studies of IMQ dermatitis in mice (GSE27628, GSE47607, GSE60804, GSE63684, GSE78057) [2,[20][21][22], human KCs treated with poly(I:C) (GSE21260) [46], human KCs treated with IL-17A (GSE12109, GSE24767, GSE27533, GSE32620, GSE36287, GSE52361, GSE53751), the Immunological Genome Project (IGP; GSE15907) [47,48], macroscopically normal human skin from control subjects without skin disease (n = 90 subjects; GSE54456; Additional file 2), laser capture microdissected human suprabasal and basal epidermis (GSE42114) [49], regenerated human epidermis organotypic cultures (GSE52953) [50], Mediterranean spotted fever eschars (GSE32993), burn wound margins 0-3 days post-injury (GSE8056) [51], and Leishmania braziliensis-infected cutaneous lesions (GSE55664) [52]. Comparisons to 35 human skin diseases were made using a database of 124 expression signatures compiled and described in a previous publication [45].…”

“…The IMQ psoriasiform phenotype has previously been evaluated using microarrays [2,[20][21][22], but to our knowledge has not yet been evaluated by RNA-seq. Previously, we used microarrays to compare cutaneous phenotypes of five psoriasis mouse models and to score the similarities and differences of such models relative to human psoriatic plaques [2].…”

Regulation of endogenous brakes to kidney fibrosis: turning the view upside down

“…Suppressing the expression of these proteins enhances organ fibrosis. This is not only true for the kidney, but similar mechanisms exist also in the liver and skin [9,10].…”

Epigenome-wide association data implicates DNA methylation-mediated genetic risk in psoriasis

“…Associations between genetic variation with expression and methylation levels have been identified in several studies, both local (cis) and distal (trans) associations of genetic variation are associate with methylation levels [9, 14, 15]. Same to a previous study on epithelial ovarian cancer, all of the SNPs were trans-MethQTL in the current study [16], while some studies reported that cis-MethQTL account for a larger proportion of MethQTL [17, 18].…”