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

Research output: Contribution to journalArticle

35 Scopus citations

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 (US)
Pages (from-to)2683-2695
Number of pages13
JournalJournal of Clinical Investigation
Volume124
Issue number6
DOIs
StatePublished - Jun 2 2014

ASJC Scopus subject areas

  • Medicine(all)

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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., Müller, F. U., Metze, D., Bunnett, N. W., Bhargava, A., Carstens, E., Furue, M., & 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