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

Abstract

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-α/IFN-γ-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.

• Authors: Li Chen, Zemin Lin, Yuting Liu, Shiqi Cao, Yueteng Huang, Xiaoqian Yang, Fenghua Zhu, Wei Tang, Shijun He, Jianping Zuo
• Journal: International immunopharmacology (Int Immunopharmacol) Vol. 91 Pg. 107334 (Feb 2021) ISSN: 1878-1705 [Electronic] Netherlands
• PMID: 33412493 (Publication Type: Journal Article)
• Copyright: Copyright © 2020. Published by Elsevier B.V.

Chemical References

• Anti-Inflammatory Agents
• Butyrates
• Chemokines
• GATA3 Transcription Factor
• GATA3 protein, human
• Gata3 protein, mouse
• LCN2 protein, human
• Lipocalin-2
• methyl 4-(adenin-9-yl)-2-hydroxybutanoate
• Lcn2 protein, mouse
• Adenine

Topics

• Adenine (analogs & derivatives, pharmacology)
• Animals
• Anti-Inflammatory Agents (pharmacology)
• Butyrates (pharmacology)
• Cell Differentiation (drug effects)
• Cell Proliferation (drug effects)
• Chemokines (metabolism)
• DNA Methylation (drug effects)
• Disease Models, Animal
• Female
• GATA3 Transcription Factor (genetics, metabolism)
• HL-60 Cells
• HaCaT Cells
• Humans
• Keratinocytes (drug effects, metabolism, pathology)
• Lipocalin-2 (genetics, metabolism)
• Mice, Inbred BALB C
• Neutrophil Infiltration (drug effects)
• Promoter Regions, Genetic (drug effects)
• Psoriasis (genetics, metabolism, pathology, prevention & control)
• Skin (drug effects, metabolism, pathology)
• Mice