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

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

研究成果: ジャーナルへの寄稿記事

32 引用 (Scopus)

抄録

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.

元の言語英語
ページ(範囲)2683-2695
ページ数13
ジャーナルJournal of Clinical Investigation
124
発行部数6
DOI
出版物ステータス出版済み - 6 2 2014

Fingerprint

Endothelin-1
Pruritus
Peptide Hydrolases
Endothelin A Receptors
Spinal Ganglia
Histamine
Endothelin-Converting Enzymes
Prurigo
Neurons
Iontophoresis
Skin
MAP Kinase Signaling System
Endosomes
Recycling
G-Protein-Coupled Receptors
Skin Diseases
Mammals
Up-Regulation
Pharmacology

All Science Journal Classification (ASJC) codes

  • Medicine(all)

これを引用

Kido-Nakahara, M., Buddenkotte, J., Kempkes, C., Ikoma, A., Cevikbas, F., Akiyama, T., ... Steinhoff, M. (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

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

:: Journal of Clinical Investigation, 巻 124, 番号 6, 02.06.2014, p. 2683-2695.

研究成果: ジャーナルへの寄稿記事

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, Müller, FU, Metze, D, Bunnett, NW, Bhargava, A, Carstens, E, Furue, M & Steinhoff, M 2014, 'Neural peptidase endothelin-converting enzyme 1 regulates endothelin 1-induced pruritus', Journal of Clinical Investigation, 巻. 124, 番号 6, pp. 2683-2695. https://doi.org/10.1172/JCI67323
Kido-Nakahara, Makiko ; Buddenkotte, Jörg ; Kempkes, Cordula ; Ikoma, Akihiko ; Cevikbas, Ferda ; Akiyama, Tasuku ; Nunes, Frank ; Seeliger, Stephan ; Hasdemir, Burcu ; Mess, Christian ; Buhl, Timo ; Sulk, Mathias ; Müller, Frank Ulrich ; Metze, Dieter ; Bunnett, Nigel W. ; Bhargava, Aditi ; Carstens, Earl ; Furue, Masutaka ; Steinhoff, Martin. / Neural peptidase endothelin-converting enzyme 1 regulates endothelin 1-induced pruritus. :: Journal of Clinical Investigation. 2014 ; 巻 124, 番号 6. pp. 2683-2695.
@article{45a259f46d3d4d77bb454da27d928c7b,
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 J{\"o}rg 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 M{\"u}ller, {Frank Ulrich} and Dieter Metze and Bunnett, {Nigel W.} and Aditi Bhargava and Earl Carstens and Masutaka Furue and Martin Steinhoff",
year = "2014",
month = "6",
day = "2",
doi = "10.1172/JCI67323",
language = "English",
volume = "124",
pages = "2683--2695",
journal = "Journal of Clinical Investigation",
issn = "0021-9738",
publisher = "The American Society for Clinical Investigation",
number = "6",

}

TY - JOUR

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

AU - Kido-Nakahara, Makiko

AU - Buddenkotte, Jörg

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 - Müller, Frank Ulrich

AU - Metze, Dieter

AU - Bunnett, Nigel W.

AU - Bhargava, Aditi

AU - Carstens, Earl

AU - Furue, Masutaka

AU - Steinhoff, Martin

PY - 2014/6/2

Y1 - 2014/6/2

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.scopus.com/inward/record.url?scp=84902166170&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84902166170&partnerID=8YFLogxK

U2 - 10.1172/JCI67323

DO - 10.1172/JCI67323

M3 - Article

C2 - 24812665

AN - SCOPUS:84902166170

VL - 124

SP - 2683

EP - 2695

JO - Journal of Clinical Investigation

JF - Journal of Clinical Investigation

SN - 0021-9738

IS - 6

ER -