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

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 5

ERK1/2 plays a central role in ET-1–induced itch in vivo.

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ERK1/2 plays a central role in ET-1–induced itch in vivo. (A) ET-1 (10 p...
(A) ET-1 (10 pmol/site) was injected i.d. into the nape of neck 30 minutes after i.p. injection of an ERK1/2 inhibitor (30 mg/kg) and/or ECE-1 inhibitor SM-19712 (25 mg/kg) (n = 9 mice/group). (B) Scratching elicited by ET-1, IL-31, and CQ was eliminated or significantly decreased in ERK inhibitor–treated (30 mg/kg BW, targets ERK1/2) or PD0325901-treated (10 mg/kg BW, targets ERK1/2 phosphorylation) mice. Total number of scratching bouts over a 30-minute period in response to i.d. injection into the cheek of mice (n = 4) of a pruritic compound panel was monitored. Compound concentrations: 100 pmol/10 μl ET-1, 100 μg/10 μl histamine, 5 nmol/10 μl IL-31, and 200 μg/10 μl CQ. (C) Amelioration of itch by ETAR blockage in mice with an AD-like phenotype. Cohorts of WT mice were treated with multiple injections of oxazolone (OXA) into the nape of neck to induce chronic pruritus. Oxazolone challenge induced a robust and persistent scratching behavior in mice (baseline was evaluated on days 12–18). On day 18, mice were i.d. injected into the nape of the neck with BQ-123 (10 nmol/100 μl or 25 nmol/100 μl). Within 30 minutes after BQ-123 injection, the total number of scratching bouts over a 30-minute period was determined. *P < 0.05; **P < 0.01; ***P < 0.001. One-way ANOVA with Dunnett’s post-hoc test.