title: 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.
authors.affiliation: Shanghai Institute of Immunology, Institute of Medical Sciences, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China;
authors.forename: Jing
authors.initials: J
authors.lastname: Bai
authors.affiliation: Shanghai Institute of Immunology, Institute of Medical Sciences, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China;
authors.forename: Zhaoyuan
authors.initials: Z
authors.lastname: Liu
authors.affiliation: Shanghai Institute of Immunology, Institute of Medical Sciences, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China;
authors.forename: Zhenyao
authors.initials: Z
authors.lastname: Xu
authors.affiliation: Shanghai Institute of Immunology, Institute of Medical Sciences, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China;
authors.forename: Fang
authors.initials: F
authors.lastname: Ke
authors.affiliation: Shanghai Institute of Immunology, Institute of Medical Sciences, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China;
authors.forename: Lingyun
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Shanghai Institute of Immunology, Institute of Medical Sciences, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China;
authors.forename: Huiyuan
authors.initials: H
authors.lastname: Zhu
authors.affiliation: Shanghai Institute of Immunology, Institute of Medical Sciences, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China;
authors.forename: Fangzhou
authors.initials: F
authors.lastname: Lou
authors.affiliation: Shanghai Institute of Immunology, Institute of Medical Sciences, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China;
authors.forename: Hong
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of Dermatology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China; and.
authors.forename: Ye
authors.initials: Y
authors.lastname: Fei
authors.affiliation: Department of Dermatology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China.
authors.forename: Yu-Ling
authors.initials: YL
authors.lastname: Shi
authors.affiliation: Shanghai Institute of Immunology, Institute of Medical Sciences, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China; honglin.wang@sjtu.edu.cn honglin_wang@shsmu.edu.cn.
authors.forename: Honglin
authors.initials: H
authors.lastname: Wang
mesh_terms: D000328:Adult; D000818:Animals; D019175:DNA Methylation; D015536:Down-Regulation / Q000235:genetics*; D004817:Epidermis / Q000473:pathology*; D044127:Epigenesis, Genetic / Q000235:genetics*; D005260:Female; D006801:Humans; D006965:Hyperplasia / Q000235:genetics* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011401:Promoter Regions, Genetic / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D011565:Psoriasis / Q000235:genetics* / Q000473:pathology; D060449:Wnt Signaling Pathway; D000094742:Secreted Frizzled-Related Proteins
chemical_list: D011518:Proto-Oncogene Proteins; C118723:SFRP4 protein, human; D000094742:Secreted Frizzled-Related Proteins