Bedeutung von Endothelin-converting enzyme-1 (ECE-1) bei der neurogenen Entzündung, Juckreiz und Schmerz
Zusammenfassung der Projektergebnisse
The sensory nervous system is ultimately involved in itch and inflammatory responses, and thus a potential target for therapy. The mechanisms how the sensory nervous system communicates with the immune system to control inflammation and itch (as in atopic dermatitis or prurigo nodularis) are very poorly understood. To study this is significant because these chronic diseases have a profound negative impact on the patient’s quality of life, and successful therapies remain an unmet medical need. Indeed, many patients with atopic dermatits and other eczematous diseases experience itch as intense and resistant to treatment due to their histamine-independent pathways. Additionally, treatments with systemic immunosuppressors or UV-therapy have - beside their costs – potentially severe side effects. My studies showed for the first time that an intracellular neural peptidase, ECE-1, regulates ET-1-induced itch and intracellular cell signaling in DRG neurons. I was able to show that ET-1, ETAR and ECE-1 are expressed on mouse DRG neurons at RNA and protein level, and can be colocalized on small- to medium-size diameter neurons, predominantly of the peptidergic (CGRP-positive) type. Upon stimulation, ET-1 induces co-localization of ET-1, ETAR and ECE-1 in endosomes of murine DRG, suggesting that ECE-1 internalizes with the ET-1/ETAR complex. ECE-1 cleaves ET-1 at a pH of 5.5, but not 7.4, indicating that ECE-1 cleaves ET-1 in acidified (early) endosomes. ET-1 induces Ca2+-mobilization and ERK1/2 phosphorylation in DRG neurons. ET-1 induced scratching behavior was markedly prolonged by ECE-1 inhibition in vivo. My results showed that ET-1 induced itch response and prolonged by ECE-1 in mice in vivo is associated with a sustained ERK1/2 induction in DRG neurons, but not by p38 or PKCδ. ERK1/2 inhibition abrogates ET-1-induced scratching behavior in vivo. Finally, in humans ET-1 and ECE-1 are upregulated in pruritic skin of patients with atopic dermatitis and chronic prurigo. Thus, my murine and human data indicate that ECE-1 is an important regulator of ET-1-induced pruritus in mice. In a translational setting, my study gives evidence that ET-1, ETAR and ECE-1 are upregulated in patients with chronic pruritus suggesting a role of this pathway in human pruritic disease. The results of my study are of interest because the identification of the ET-1 itch signaling pathways will be of interest to understand the neurobiological pathology of chronic itch. Further, the results of my study could be used as a basis to study the effect of different pharmaceutical inhibitors within the ET-1 depending pathways to inhibit chronic itch. However these effects will be needed to study in further different mice models first before first translational experiments can be performed within the human system.
Projektbezogene Publikationen (Auswahl)
- Anatomy and neurophysiology of pruritus. Semin Cutan Med Surg. 2011 Jun;30(2):64-70
Ikoma A et al.
