Epigenetic downregulation of SFRP4 contributes to epidermal hyperplasia in psoriasis

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 plaque...

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Bibliographic Details
Published in:The Journal of immunology (1950) 2015-05, Vol.194 (9), p.4185-4198
Main Authors: Bai, Jing, Liu, Zhaoyuan, Xu, Zhenyao, Ke, Fang, Zhang, Lingyun, Zhu, Huiyuan, Lou, Fangzhou, Wang, Hong, Fei, Ye, Shi, Yu-Ling, Wang, Honglin
Format: Article
Language:English
Subjects:
Adult
Animals
DNA Methylation
Down-Regulation - genetics
Epidermis - pathology
Epigenesis, Genetic - genetics
Female
Humans
Hyperplasia - genetics
Hyperplasia - pathology
Male
Mice
Mice, Inbred C57BL
Promoter Regions, Genetic - genetics
Proto-Oncogene Proteins - genetics
Psoriasis - genetics
Psoriasis - pathology
Wnt Signaling Pathway
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Summary: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.
ISSN:0022-1767
1550-6606
DOI:10.4049/jimmunol.1403196