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.
Highlights
Endothelin-1 (ET-1) is well known as the most potent vasoconstrictor, and can evoke histamineindependent pruritus
The expression levels of ET-1 were significantly increased in the epidermis of IMQ-induced psoriasiform dermatitis in mouse (Fig. 1a)
To examine the regulation of ET-1 expression in the epidermis in psoriasis, we investigated the expression of ET-1 in human keratinocytes after stimulation with psoriasis-related cytokines such as IL-17A and TNF-α
Summary
Endothelin-1 (ET-1) is well known as the most potent vasoconstrictor, and can evoke histamineindependent pruritus. Topical application of selective endothelin A receptor (ETAR) antagonist ambrisentan significantly attenuated the development of IMQ-induced psoriasiform dermatitis and 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. The topical application of imiquimod (IMQ), a toll-like receptor (TLR)[7] ligand and a potent immune activator, induces skin inflammation in mice with features similar to psoriasis via the IL-17/23 axis[6]. In this model, mice are topically applied with IMQ cream for 5 or 6 days. We analysed whether ambrisentan or bosentan modulates the IMQ-induced murine model of psoriasiform dermatitis
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