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 histamineindependent 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.

Regulation of Skin Barrier Function via Competition between AHR Axis versus IL-13/IL-4‒JAK‒STAT6/STAT3 Axis: Pathogenic and Therapeutic Implications in Atopic Dermatitis

“…Thus, endothelin 1 is possibly involved in the chronic (namely complexed or intermingled) immune response in inflammatory skin diseases [ 172 , 174 ]. In keeping with this notion, topical application of endothelin receptor antagonist was found to attenuate mite-induced dermatitis [ 62 ] as well as imiquimod-induced psoriasiform skin inflammation [ 175 ]. Notably, there is a mutual feedforward regulatory circuit between IL-25 and endothelin 1.…”

Interleukin-22 and keratinocytes; pathogenic implications in skin inflammation

“…Thus, endothelin 1 is one of the cutaneous factors promoting IL-22 production [56,58]. In line with this notion, topical application of endothelin receptor antagonist alleviates not only mite-induced dermatitis [59] but also imiquimod-induced psoriasiform skin inflammation [60]. Notably, there is a mutual feedforward regulatory circuit between IL-25 and endothelin 1-IL-25 upregulates the expression of endothelin 1, while endothelin 1 also upregulates the production of IL-25 in keratinocytes [54].…”

Onset of rupioid psoriasis after vasodilatory regimen initiation in a patient with pulmonary arterial hypertension

“…Lastly, macitentan, a mixed endothelin receptor antagonist with greater selectivity for endothelin A (ETA) than endothelin B (ETB) receptors, 10 would be expected to have anti-psoriatic properties through antagonism of both the endothelin-1-mediated keratinocyte proliferation 11 and pro-psoriatic inflammatory cascade stimulation. 12 Psoriatic lesions have increased expression of endothelin 1, and topical application of a selective ETA receptor antagonist (ambrisentan) attenuates imiquimod-induced psoriasiform inflammation development. 12 The strong vasodilating properties of systemic macitentan could have overcome its anti-proliferative and anti-inflammatory effects, as demonstrated during in-vitro experimentation.…”

“… 12 Psoriatic lesions have increased expression of endothelin 1, and topical application of a selective ETA receptor antagonist (ambrisentan) attenuates imiquimod-induced psoriasiform inflammation development. 12 The strong vasodilating properties of systemic macitentan could have overcome its anti-proliferative and anti-inflammatory effects, as demonstrated during in-vitro experimentation. Interestingly, selective ETB receptor antagonism produces no therapeutic effect on imiquimod-induced psoriasiform dermatitis.…”

“…Interestingly, selective ETB receptor antagonism produces no therapeutic effect on imiquimod-induced psoriasiform dermatitis. 12 Also, unlike ETA receptor blockade, ETB receptor antagonism enhances dendritic cell mediated immune responses. 12 The differential degree of endothelin receptor inhibition by macitentan may produce complex interactions in various tissues resulting in psoriasis induction.…”