Heim Xavier, Bermudez Julien, Joshkon Ahmad, Kaspi Elise, Bachelier Richard, Nollet Marie, Vélier Mélanie, Dou Laetitia, Brodovitch Alexandre, Foucault-Bertaud Alexandrine, Leroyer Aurelie S, Benyamine Audrey, Daumas Aurélie, Granel Brigitte, Sabatier Florence, Dignat-George Françoise, Blot-Chabaud Marcel, Bardin Nathalie
Aix Marseille Univ, INSERM, INRAE, C2VN, Marseille, France; Service d'immunologie, Biogénopôle, Hôpital de la Timone, Assistance Publique des Hôpitaux de Marseille (AP-HM), Marseille, France.
Aix Marseille Univ, INSERM, INRAE, C2VN, Marseille, France.
J Invest Dermatol. 2022 Dec;142(12):3200-3210.e5. doi: 10.1016/j.jid.2022.03.038. Epub 2022 Jun 9.
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.
最近有研究表明，CD146通过调节Wnt信号通路参与系统性硬化症的皮肤纤维化过程。由于Wnt与ROS信号之间的相互作用在纤维化中起主要作用，我们推测在系统性硬化症中，CD146可能调节Wnt/ROS信号串扰。通过对CD146野生型或敲除型小鼠胚胎成纤维细胞进行转录组学和蛋白质印迹分析，我们发现缺乏CD146时呈现出促经典Wnt特征，而恢复CD146表达后该特征则被逆转。我们发现敲除细胞中的ROS含量升高，与野生型小鼠相比，敲除小鼠皮肤切片中的DNA氧化损伤增加。我们还发现，ROS仅在野生型细胞中增加CD146及其非经典Wnt配体WNT5A。在人类中，系统性硬化症患者的成纤维细胞呈现出较高的ROS含量并表达CD146，而对照成纤维细胞则不表达。此外，在两种人类成纤维细胞中，ROS均上调CD146及其配体。当CD146沉默时，博来霉素诱导的WNT5A表达增加被消除。我们展示了系统性硬化症中Wnt与ROS信号之间的相互作用，该相互作用受CD146调节，CD146促进非经典Wnt信号通路并阻止ROS信号，为创新治疗策略开辟了道路。
