2020.09.18 Journal club

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

Makiko Kido-Nakahara1, Bing Wang, Fumitaka Ohno, Gaku Tsuji, Dugarmaa Ulzii, Masaki Takemura, Masutaka Furue, Takeshi Nakahara

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.