Inhibition of mite‐induced dermatitis, pruritus, and nerve sprouting in mice by the endothelin receptor antagonist bosentan

Abstract

Background: Endothelin-1 (EDN1) can evoke histamine-independent pruritus in mammals and is upregulated in the lesional epidermis of atopic dermatitis (AD). EDN1 increases the production of interleukin 25 (IL-25) from keratinocytes to accelerate T helper type 2 immune deviation. Plasma EDN1 levels are positively correlated with the clinical severity and itch intensity of AD. Therefore, we hypothesized that the inhibition of EDN1 might be useful for treating atopic inflammation and itch and investigated the effects of the topical application of the EDN1 receptor antagonist bosentan on the skin inflammation and itch in a murine AD model. Methods: We analyzed the mite-induced AD-like NC/Nga murine model, which was topically applied with bosentan or ethanol control every day for 3 weeks. We also subjected in vitro primary sensory neuron culture systems to nerve elongation and branching assays after EDN1 stimulation. Results: Topical application of bosentan significantly attenuated the development of mite-induced AD-like skin inflammation, dermatitis scores, ear thickness, scratching bouts, and serum level of thymus and activation-regulated chemokine in NC/Nga mice. Bosentan application also significantly reduced the gene expression of Il13, Il17, and Ifng in the treated lesions. Histologically, the number of infiltrated dermal cells, the epidermal EDN1 expression, and the number of intraepidermal nerve fibers were significantly inhibited upon bosentan application. While EDN1 significantly elongated the neurites of dorsal root ganglion cells in a dose-and time-dependent manner, bosentan treatment attenuated this. Conclusions: EDN1 plays a significant role in mite-induced inflammation and itch. Topical bosentan is a potential protective candidate for AD.

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

“…Its expression is elevated in the lesional skin of AD [ 22 ]. IL-31 induces elongation and branching of sensory nerve fibers [ 61 , 62 ]. Notably, the administration of IL-31 evokes scratching behavior in mouse, dog, and monkey, as well as pruritus in human [ 59 ].…”

“…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].…”

Basics and recent advances in the pathophysiology of atopic dermatitis

“…Furthermore, simultaneous blockade of H1R and H4R was shown to be more effective in reducing itch and inflammation than either alone. 95 However, as noted above, histamine appears to have a limited role in causing itch in AD.…”

“…66,92,93 In fact, we recently reported that the topical application of ET-1 receptor antagonist significantly attenuated the development of mite-induced AD-like skin inflammation, and reduced dermatitis scores and scratching bouts in NC/Nga mice. 93…”