Detection of native, activated Notch receptors in normal human apocrine-bearing skin and in hidradenitis suppurativa.
acne inversa
gamma-secretase
hidradenitis suppurativa
immunohistochemistry
notch
Journal
Experimental dermatology
ISSN: 1600-0625
Titre abrégé: Exp Dermatol
Pays: Denmark
ID NLM: 9301549
Informations de publication
Date de publication:
07 Dec 2023
07 Dec 2023
Historique:
revised:
30
10
2023
received:
06
07
2023
accepted:
05
11
2023
medline:
7
12
2023
pubmed:
7
12
2023
entrez:
7
12
2023
Statut:
aheadofprint
Résumé
Notch signalling has generated considerable interest as a pathogenetic factor and a drug target in a range of human diseases. The gamma-secretase complex is crucial in the activation of Notch receptors by cleaving the intracellular domain allowing nuclear translocation. In recent years several mutations in gamma-secretase components have been discovered in patients with familial hidradenitis suppurativa (HS). This has led to hypotheses that impaired Notch signalling could be an important driver for HS in general, not only in the monogenic variants. However, no study has examined in situ Notch activation per se in HS, and some reports with conflicting results have instead been based on expression of Notch receptors or indirect measures of Notch target gene expression. In this study we established immunostaining protocols to identify native, activated Notch receptors in human skin tissue. The ability to detect changes in Notch activation was confirmed with an ex vivo skin organ model in which signal was reduced or obliterated in tissue exposed to a gamma-secretase inhibitor. Using these methods on skin biopsies from healthy volunteers and a general HS cohort we demonstrated for the first time the distribution of active Notch signalling in human apocrine-bearing skin. Quantification of activated NOTCH1 & NOTCH2 revealed similar levels in non-lesional and peri-lesional HS to that of healthy controls, thus ruling out a general defect in Notch activation in HS patients. We did find a variable but significant reduction of activated Notch in epidermis of lesional HS with a distribution that appeared related to the extent of surrounding tissue inflammation.
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : AbbVie
Organisme : Arne E. Ingles endowment
Organisme : Norwegian Society of Dermatology (NFDV)
Organisme : Novartis
Informations de copyright
© 2023 The Authors. Experimental Dermatology published by John Wiley & Sons Ltd.
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