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

• 作 者: Yishan Ye Laure Ricard Lama Siblany Nicolas Stocker Frédéric De Vassoigne Eolia Brissot Baptiste Lamarthée Arsène Mekinian Mohamad Mohty Béatrice Gaugler Florent Malard
• 机 构: Sorbonne Université, INSERM, Centre de Recherche Saint-Antoine (CRSA), Paris F-75012, France;Bone Ma
• 出 处: 药学学报（英文版）
• 发表日期: 2020年6期
• 关键词: Arsenic trioxide Plasmacytoid dendritic cell Immunotherapy Systemic sclerosis IF

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.