CD146 at the Interface between Oxidative Stress and the Wnt Signaling Pathway in Systemic Sclerosis

Autor: Xavier, Heim, Julien, Bermudez, Ahmad, Joshkon, Elise, Kaspi, Richard, Bachelier, Marie, Nollet, Mélanie, Vélier, Laetitia, Dou, Alexandre, Brodovitch, Alexandrine, Foucault-Bertaud, Aurelie S, Leroyer, Audrey, Benyamine, Aurélie, Daumas, Brigitte, Granel, Florence, Sabatier, Françoise, Dignat-George, Marcel, Blot-Chabaud, Nathalie, Bardin
Přispěvatelé: Centre recherche en CardioVasculaire et Nutrition = Center for CardioVascular and Nutrition research (C2VN), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Marseille medical genetics - Centre de génétique médicale de Marseille (MMG), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de Biologie Cellulaire [Hôpital de la Timone - APHM], Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE)
Jazyk: angličtina
Rok vydání: 2022
Předmět:
Zdroj: Journal of Investigative Dermatology
Journal of Investigative Dermatology, 2022, 142 (12), pp.3200-3210.e5. ⟨10.1016/j.jid.2022.03.038⟩
ISSN: 0022-202X
1523-1747
DOI: 10.1016/j.jid.2022.03.038⟩
Popis: International audience; CD146 involvement was recently described in skin fibrosis of systemic sclerosis through its regulation of the Wnt pathway. Because the interaction between Wnt and ROS signaling plays a major role in fibrosis, we hypothesized that in systemic sclerosis, CD146 may regulate Wnt/ROS crosstalk. Using a transcriptomic and western blot analysis performed on CD146 wild-type or knockout mouse embryonic fibroblasts, we showed a procanonical Wnt hallmark in the absence of CD146 that is reversed when CD146 expression is restored. We found an elevated ROS content in knockout cells and an increase in DNA oxidative damage in the skin sections of knockout mice compared with those of wild-type mice. We also showed that ROS increased CD146 and its noncanonical Wnt ligand, WNT5A, only in wild-type cells. In humans, fibroblasts from patients with systemic sclerosis presented higher ROS content and expressed CD146, whereas control fibroblasts did not. Moreover, CD146 and its ligand were upregulated by ROS in both human fibroblasts. The increase in bleomycin-induced WNT5A expression was abrogated when CD146 was silenced. We showed an interplay between Wnt and ROS signaling in systemic sclerosis, regulated by CD146, which promotes the noncanonical Wnt pathway and prevents ROS signaling, opening the way for innovative therapeutic strategies.
Databáze: OpenAIRE
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