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Neural peptidase endothelin-converting enzyme 1 regulates endothelin 1–induced pruritus
Makiko Kido-Nakahara, … , Masutaka Furue, Martin Steinhoff
Makiko Kido-Nakahara, … , Masutaka Furue, Martin Steinhoff
Published May 8, 2014
Citation Information: J Clin Invest. 2014;124(6):2683-2695. https://doi.org/10.1172/JCI67323.
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Research Article Neuroscience Article has an altmetric score of 16

Neural peptidase endothelin-converting enzyme 1 regulates endothelin 1–induced pruritus

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Abstract

In humans, pruritus (itch) is a common but poorly understood symptom in numerous skin and systemic diseases. Endothelin 1 (ET-1) evokes histamine-independent pruritus in mammals through activation of its cognate G protein–coupled receptor endothelin A receptor (ETAR). Here, we have identified neural endothelin–converting enzyme 1 (ECE-1) as a key regulator of ET-1–induced pruritus and neural signaling of itch. We show here that ETAR, ET-1, and ECE-1 are expressed and colocalize in murine dorsal root ganglia (DRG) neurons and human skin nerves. In murine DRG neurons, ET-1 induced internalization of ETAR within ECE-1–containing endosomes. ECE-1 inhibition slowed ETAR recycling yet prolonged ET-1–induced activation of ERK1/2, but not p38. In a murine itch model, ET-1–induced scratching behavior was substantially augmented by pharmacological ECE-1 inhibition and abrogated by treatment with an ERK1/2 inhibitor. Using iontophoresis, we demonstrated that ET-1 is a potent, partially histamine-independent pruritogen in humans. Immunohistochemical evaluation of skin from prurigo nodularis patients confirmed an upregulation of the ET-1/ETAR/ECE-1/ERK1/2 axis in patients with chronic itch. Together, our data identify the neural peptidase ECE-1 as a negative regulator of itch on sensory nerves by directly regulating ET-1–induced pruritus in humans and mice. Furthermore, these results implicate the ET-1/ECE-1/ERK1/2 pathway as a therapeutic target to treat pruritus in humans.

Authors

Makiko Kido-Nakahara, Jörg Buddenkotte, Cordula Kempkes, Akihiko Ikoma, Ferda Cevikbas, Tasuku Akiyama, Frank Nunes, Stephan Seeliger, Burcu Hasdemir, Christian Mess, Timo Buhl, Mathias Sulk, Frank-Ulrich Müller, Dieter Metze, Nigel W. Bunnett, Aditi Bhargava, Earl Carstens, Masutaka Furue, Martin Steinhoff

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Figure 6

Increase of ET-1 and ETAR in pruritic human skin and independence of ET-1–evoked itch from H1R function in humans.

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Increase of ET-1 and ETAR in pruritic human skin and independence of ET-...
(A) Localization of ET-1, ETAR, and ECE-1 in peripheral nerves of skin from patients with PN. Immunoreactivity was examined with IHC using serial sections. Positive staining for ETAR and ET-1 and (arrows) was detected for PGP9.5+ cutaneous sensory nerve fibers. Scale bars: 50 μm. (B) Staining for ET-1 was significantly enhanced in the epidermis of PN-affected skin compared with that of healthy skin (NHS) and AD. Samples from AD patients did not show enhanced ET-1 staining in keratinocytes, but due to acanthosis, the total harbored ET-1 may be increased when compared with healthy skin. Keratinocytes stained positively for ET-1, but fibroblasts stained negatively for ET-1. (C) Time course of itch intensity (0: no itch, 10: worst imaginable itch) for a 10-minute period after termination of a 60-second iontophoresis with histamine (white circles) and ET-1 (black circles) on the forearm skin of healthy human subjects (n = 6) who were orally administered a 60-mg fexofenadine tablet (antihistamine H1R blocker) 3 hours before. ET-1 induced itch partly but not completely independently of histamine release in humans, because the antihistamine H1R blocker did not significantly block itch from 0–4 minutes, but ameliorated itch perception of volunteers from 4 minutes until the end of monitoring. Agonist-only treatment controls are shown for ET-1 (black squares) and histamine (white squares), respectively. *P < 0.05; **P < 0.01; ***P < 0.001; error bars indicate the SEM.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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