Topical application of endothelin receptor a antagonist attenuates imiquimod-induced psoriasiform skin inflammation.

Abstract

Endothelin-1 (ET-1) is well known as the most potent vasoconstrictor, and can evoke histamine-independent pruritus. Recently, its involvement in cutaneous inflammation has begun to draw attention. The upregulation of ET-1 expression in the epidermis of human psoriasis patients has been reported. It was also demonstrated that ET-1 can stimulate dendritic cells to induce Th17/1 immune responses. However, the role of the interaction between ET-1 and ET-1 receptors in the pathogenesis of psoriasis remains elusive. Here, we investigated the effects of ET-1 receptor antagonist on imiquimod (IMQ) -induced psoriasiform dermatitis in mouse. Psoriasis-related cytokines such as IL-17A and TNF-α induced ET-1 expression in human keratinocytes. Topical application of selective endothelin A receptor (ETAR) antagonist ambrisentan significantly attenuated the development of IMQ-induced psoriasiform dermatitis and also significantly inhibited the histological inflammation and cytokine expression (TNF-α, IL-12p40, IL-12 p19, and IL-17) in the lesional skin of the mouse model. Furthermore, topical application of ambrisentan suppressed phenotypic and functional activation of dendritic cells in lymph nodes. Our findings indicate that the ET-1 and ETAR axis plays an important role in the pathogenesis of psoriasis and is a potential therapeutic target for treating psoriasis.

• Authors: Takeshi Nakahara, Makiko Kido-Nakahara, Dugarmaa Ulzii, Sho Miake, Kei Fujishima, Sawako Sakai, Takahito Chiba, Gaku Tsuji, Masutaka Furue
• Journal: Scientific reports (Sci Rep) Vol. 10 Issue 1 Pg. 9510 (06 11 2020) ISSN: 2045-2322 [Electronic] England
• PMID: 32528072 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Cytokines
• Endothelin Receptor Antagonists
• Endothelin-1
• Phenylpropionates
• Pyridazines
• Receptors, Endothelin
• ambrisentan
• Imiquimod

Topics

• Administration, Topical
• Animals
• Cytokines (metabolism)
• Endothelin Receptor Antagonists (administration & dosage, pharmacology, therapeutic use)
• Endothelin-1 (metabolism)
• Gene Expression Regulation (drug effects)
• Humans
• Imiquimod (adverse effects)
• Mice
• Phenylpropionates (administration & dosage, pharmacology, therapeutic use)
• Psoriasis (chemically induced, drug therapy, metabolism, prevention & control)
• Pyridazines (administration & dosage, pharmacology, therapeutic use)
• Receptors, Endothelin (metabolism)
• Skin (drug effects, pathology)