DZ2002 alleviates psoriasis-like skin lesions via differentially regulating methylation of GATA3 and LCN2 promoters

doi:10.1016/j.intimp.2020.107334

	DZ2002 alleviates psoriasis-like skin lesions via differentially regulating methylation of GATA3 and LCN2 promoters
	Chen, Li 1,2; Lin, Zemin 1; Liu, Yuting 1,2; Cao, Shiqi 1,2; Huang, Yueteng 3; Yang, Xiaoqian 1; Zhu, Fenghua 1; Tang, Wei 2,4; He, Shijun 1,2; Zuo, Jianping 1,2,3
刊名	INTERNATIONAL IMMUNOPHARMACOLOGY
	2021-02-01
卷号	91 页码:12
关键词	DZ2002 Psoriasis DNA methylation Keratinocyte Inflammatory infiltration
ISSN号	1567-5769
DOI	10.1016/j.intimp.2020.107334
通讯作者	He, Shijun(heshijun@simm.ac.cn) ; Zuo, Jianping(jpzuo@simm.ac.cn)
英文摘要	Psoriasis is the most prevalent inflammatory skin disorders, affecting 1-3% of the worldwide population. We previously reported that topical application of methyl 4-(adenin-9-yl)-2-hydroxybutanoate (DZ2002), a reversible S-adenosyl-l-homocysteine hydrolase (SAHH) inhibitor, was a viable treatment in murine psoriatic skin inflammation. In current study, we further explored the mechanisms of DZ2002 on keratinocyte dysfunction and skin infiltration, the key pathogenic events in psoriasis. We conducted genome-wide DNA methylation analysis in skin tissue from imiquimod (IMQ)-induced psoriatic and normal mice, demonstrated that topical administration of DZ2002 directly rectified aberrant DNA methylation pattern in epidermis and dermis of psoriatic skin lesion. Especially, DZ2002 differentially regulated DNA methylation of GATA3 and LCN2 promoters, which maintained keratinocytes differentiation and reduced inflammatory infiltration in psoriatic skin respectively. In vitro studies in TNF-alpha/IFN-gamma-elicited HaCaT manifested that DZ2002 treatment rectified compromised keratinocyte differentiation via GATA3 enhancement and abated chemokine expression by reducing LCN2 production under inflammatory stimulation. Chemotaxis assays conducted on dHL-60 cells confirmed that suppression of LCN2 expression by DZ2002 was accompanied by CXCR1 and CXCR2 downregulation, and contributed to the inhibition of CXCL8-driven neutrophils migration. In conclusion, therapeutic benefits of DZ2002 are achieved through differentially regulating DNA methylation of GATA3 and LCN2 promoters in psoriatic skin lesion, which efficiently interrupt the pathogenic interplay between keratinocytes and infiltrating immune cells, thus maintains epidermal keratinocytes differentiation and prevents dermal immune infiltration in psoriatic skin.
资助项目	National Nature Science foundation of China[81871240] ; National Science & Technology Major Project New Drug Creation and Manufacturing Program, China[2018ZX09711002-014-001] ; Personalized Medicines-Molecular Signature-based Drug Discovery and Development, Strategic Priority Research Program of the Chinese Academy of Sciences[XDA12020369] ; Personalized Medicines-Molecular Signature-based Drug Discovery and Development, Strategic Priority Research Program of the Chinese Academy of Sciences[XDA12020107]
WOS研究方向	Immunology ; Pharmacology & Pharmacy
语种	英语
出版者	ELSEVIER
WOS记录号	WOS:000613920000004
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/295916]
专题	中国科学院上海药物研究所
通讯作者	He, Shijun; Zuo, Jianping
作者单位	1.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Lab Immunopharmacol, 555 Zuchongzhi Rd, Shanghai 201203, Peoples R China 2.Univ Chinese Acad Sci, 19A Yuquan Rd, Beijing 100049, Peoples R China 3.Shanghai Univ Tradit Chinese Med, Lab Immunol & Virol, Shanghai 201203, Peoples R China 4.Chinese Acad Sci, Shanghai Inst Mat Med, Lab Antiinflammat, Shanghai, Peoples R China
推荐引用方式 GB/T 7714	Chen, Li,Lin, Zemin,Liu, Yuting,et al. DZ2002 alleviates psoriasis-like skin lesions via differentially regulating methylation of GATA3 and LCN2 promoters[J]. INTERNATIONAL IMMUNOPHARMACOLOGY,2021,91:12.
APA	Chen, Li.,Lin, Zemin.,Liu, Yuting.,Cao, Shiqi.,Huang, Yueteng.,...&Zuo, Jianping.(2021).DZ2002 alleviates psoriasis-like skin lesions via differentially regulating methylation of GATA3 and LCN2 promoters.INTERNATIONAL IMMUNOPHARMACOLOGY,91,12.
MLA	Chen, Li,et al."DZ2002 alleviates psoriasis-like skin lesions via differentially regulating methylation of GATA3 and LCN2 promoters".INTERNATIONAL IMMUNOPHARMACOLOGY 91(2021):12.