Arsenic trioxide induces regulatory functions of plasmacytoid dendritic cells through interferon-α inhibition

• 作者: Arsène Mekinian Baptiste Lamarthée Béatrice Gaugler Eolia Brissot Florent Malard Frédéric De Vassoigne Lama Siblany Laure Ricard Mohamad Mohty Nicolas Stocker Yishan Ye
• 来源期刊: 药学学报（英文版）
• 年，卷（期）: 2020,（6）
• 所属期刊栏目: Original articles
• 页码范围: 1061-1072
• 页数: 12页
• 语种: 英文

摘要

Arsenic trioxide (As2O3) is recently found to have therapeutic potential in systemic sclerosis (SSc),a life-threatening multi-system fibrosing autoimmune disease with type Ⅰ interferon (IFN-I) signature.Chronically activated plasmacytoid dendritic cells (pDCs) are responsible for IFN-I secretion and are closely related with fibrosis establishment in SSc.In this study,we showed that high concentrations of As2O3 induced apoptosis of pDCs via mitochondrial pathway with increased BAX/BCL-2 ratio,while independent of reactive oxygen species generation.Notably,at clinical relevant concentrations,As2O3 preferentially inhibited 1FN-α secretion as compared to other cytokines such as TNF-α,probably due to potent down-regulation of the total protein and mRNA expression,as well as phosphorylation of the interferon regulatory factor 7 (IRF7).In addition,As2O3 induced a suppressive phenotype,and in combination with cytokine inhibition,it down-regulated pDCs' capacity to induce CD4+ T cell proliferation,Th1/Th22 polarization,and B cell differentiation towards plasmablasts.Moreover,chronically activated pDCs from SSc patients were not resistant to the selective IFN-α inhibition,and regulatory phenotype induced by As2O3.Collectively,our data suggest that As2O3 could target pDCs and exert its treatment efficacy in SSc,and more autoimmune disorders with IFN-I signature.