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.

Plasma endothelin-1 levels during exacerbation of atopic dermatitis

“…18 Recently, an intracellular neural peptidase-1 (ECE-1) was identified as a key regulator of ET-1-induced pruritus and neural signaling of itch. 19 Analysis of our results indicated that ET-1 might have some pathophysiologic pruritogenic involvement in AD, at least during AD exacerbation.…”

Molecular and cellular mechanisms that initiate pain and itch

“…Application of ET-1 to human forearm by iontophoresis elicits itching in human subjects. Furthermore, the expression of ET-1 is increased in the epidermis of patients with chronic pruritic diseases [94]. In mice, intradermal (i.d.)…”

House Dust Mites Induce Production of Endothelin-1 and Matrix Metalloproteinase-9 in Keratinocytes via Proteinase-Activated Receptor-2 Activation

“…ET-1 has been shown to be a potent, partially histamine-independent pruritogen in humans [18]. Upregulation of ET-1 expression was reported in the epidermis of patients with AD compared with that of healthy controls [19].…”

“…Endothelin-1 (ET-1) is a 21-amino acid peptide which activates specific G protein-coupled ET A and ET B receptors [17]. ET-1 was originally characterized as a potent vasoconstrictor, but can also evoke itch sensations in humans [18]. Immunohistochemical studies have revealed the upregulation of ET-1 expression in the epidermis of patients with AD [19].…”