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

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

Research output: Contribution to journalArticleResearchpeer-review

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.
Original languageEnglish
Pages (from-to)2683 - 2695
Number of pages13
JournalJournal of Clinical Investigation
Volume124
Issue number6
DOIs
Publication statusPublished - 2014

Cite this

Kido-Nakahara, M., Buddenkotte, J., Kempkes, C., Ikoma, A., Cevikbas, F., Akiyama, T., ... Steinhoff, M. S. (2014). Neural peptidase endothelin-converting enzyme 1 regulates endothelin 1-induced pruritus. Journal of Clinical Investigation, 124(6), 2683 - 2695. https://doi.org/10.1172/JCI67323
Kido-Nakahara, Makiko ; Buddenkotte, Jorg ; Kempkes, Cordula ; Ikoma, Akihiko ; Cevikbas, Ferda ; Akiyama, Tasuku ; Nunes, Frank ; Seeliger, Stephan ; Hasdemir, Burcu ; Mess, Christian ; Buhl, Timo ; Sulk, Mathias ; Muller, Frank-Ulrich ; Metze, Dieter ; Bunnett, Nigel William ; Bhargava, Aditi ; Carstens, Earl ; Furue, Masutaka ; Steinhoff, Martin S. / Neural peptidase endothelin-converting enzyme 1 regulates endothelin 1-induced pruritus. In: Journal of Clinical Investigation. 2014 ; Vol. 124, No. 6. pp. 2683 - 2695.
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title = "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.",
author = "Makiko Kido-Nakahara and Jorg Buddenkotte and Cordula Kempkes and Akihiko Ikoma and Ferda Cevikbas and Tasuku Akiyama and Frank Nunes and Stephan Seeliger and Burcu Hasdemir and Christian Mess and Timo Buhl and Mathias Sulk and Frank-Ulrich Muller and Dieter Metze and Bunnett, {Nigel William} and Aditi Bhargava and Earl Carstens and Masutaka Furue and Steinhoff, {Martin S}",
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Kido-Nakahara, M, Buddenkotte, J, Kempkes, C, Ikoma, A, Cevikbas, F, Akiyama, T, Nunes, F, Seeliger, S, Hasdemir, B, Mess, C, Buhl, T, Sulk, M, Muller, F-U, Metze, D, Bunnett, NW, Bhargava, A, Carstens, E, Furue, M & Steinhoff, MS 2014, 'Neural peptidase endothelin-converting enzyme 1 regulates endothelin 1-induced pruritus' Journal of Clinical Investigation, vol. 124, no. 6, pp. 2683 - 2695. https://doi.org/10.1172/JCI67323

Neural peptidase endothelin-converting enzyme 1 regulates endothelin 1-induced pruritus. / Kido-Nakahara, Makiko; Buddenkotte, Jorg; Kempkes, Cordula; Ikoma, Akihiko; Cevikbas, Ferda; Akiyama, Tasuku; Nunes, Frank; Seeliger, Stephan; Hasdemir, Burcu; Mess, Christian; Buhl, Timo; Sulk, Mathias; Muller, Frank-Ulrich; Metze, Dieter; Bunnett, Nigel William; Bhargava, Aditi; Carstens, Earl; Furue, Masutaka; Steinhoff, Martin S.

In: Journal of Clinical Investigation, Vol. 124, No. 6, 2014, p. 2683 - 2695.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Neural peptidase endothelin-converting enzyme 1 regulates endothelin 1-induced pruritus

AU - Kido-Nakahara, Makiko

AU - Buddenkotte, Jorg

AU - Kempkes, Cordula

AU - Ikoma, Akihiko

AU - Cevikbas, Ferda

AU - Akiyama, Tasuku

AU - Nunes, Frank

AU - Seeliger, Stephan

AU - Hasdemir, Burcu

AU - Mess, Christian

AU - Buhl, Timo

AU - Sulk, Mathias

AU - Muller, Frank-Ulrich

AU - Metze, Dieter

AU - Bunnett, Nigel William

AU - Bhargava, Aditi

AU - Carstens, Earl

AU - Furue, Masutaka

AU - Steinhoff, Martin S

PY - 2014

Y1 - 2014

N2 - 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.

AB - 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.

UR - http://www.jci.org/articles/view/67323/pdf

U2 - 10.1172/JCI67323

DO - 10.1172/JCI67323

M3 - Article

VL - 124

SP - 2683

EP - 2695

JO - Journal of Clinical Investigation

JF - Journal of Clinical Investigation

SN - 0021-9738

IS - 6

ER -

Kido-Nakahara M, Buddenkotte J, Kempkes C, Ikoma A, Cevikbas F, Akiyama T et al. Neural peptidase endothelin-converting enzyme 1 regulates endothelin 1-induced pruritus. Journal of Clinical Investigation. 2014;124(6):2683 - 2695. https://doi.org/10.1172/JCI67323