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

• Main Authors: Yishan Ye (Author), Laure Ricard (Author), Lama Siblany (Author), Nicolas Stocker (Author), Frédéric De Vassoigne (Author), Eolia Brissot (Author), Baptiste Lamarthée (Author), Arsène Mekinian (Author), Mohamad Mohty (Author), Béatrice Gaugler (Author), Florent Malard (Author)
• Format: Book
• Published: Elsevier, 2020-06-01T00:00:00Z.
• Subjects: article
• Online Access: Connect to this object online.
• Notes: 2211-3835; 10.1016/j.apsb.2020.01.016
• Keywords: Arsenic trioxide; Plasmacytoid dendritic cell; Immunotherapy; Systemic sclerosis; IFN-I; Therapeutics. Pharmacology; RM1-950
• Source: Acta Pharmaceutica Sinica B, Vol 10, Iss 6, Pp 1061-1072 (2020)

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 IFN-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.