Original articles
Yishan Ye, Laure Ricard, Lama Siblany, Nicolas Stocker, Frédéric De Vassoigne, Eolia Brissot, Baptiste Lamartheé, Arsène Mekinian, Mohamad Mohty, Béatrice Gaugler, Florent Malard. Arsenic trioxide induces regulatory functions of plasmacytoid dendritic cells through interferon-α inhibition[J]. Acta Pharmaceutica Sinica B, 2020, 10(6): 1061-1072

Arsenic trioxide induces regulatory functions of plasmacytoid dendritic cells through interferon-α inhibition
Yishan Yea,b, Laure Ricarda, Lama Siblanya, Nicolas Stockera, Frédéric De Vassoignec, Eolia Brissota,c, Baptiste Lamartheéa, Arsène Mekiniana,d, Mohamad Mohtya,c, Béatrice Gauglera, Florent Malarda,c
a Sorbonne Université, INSERM, Centre de Recherche Saint-Antoine(CRSA), Paris F-75012, France;
b Bone Marrow Transplantation Center, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, China;
c AP-HP, Hôpital Saint-Antoine, Service d'Hématologie Clinique et Thérapie Cellulaire, Paris F-75012, France;
d AP-HP, Hôpital Saint-Antoine, Service de Médecine Interne et de l'Inflammation-(DHU i2B), Paris F-75012, France
Abstract:
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-a 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-a 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.
Key words:    Arsenic trioxide    Plasmacytoid dendritic cell    Immunotherapy    Systemic sclerosis    IFN-I   
Received: 2019-07-07     Revised: 2019-12-04
DOI: 10.1016/j.apsb.2020.01.016
Funds: The authors acknowledge the Association for Training, Education and Research in Hematology, Immunology and Transplantation for the generous and continuous support to the research work. Yishan Ye thanks to China Scholarship Council for financial support (CSC No. 201606320257, China). Mohamad Mohty thanks Prof. J.V. Melo for critical reading of the manuscript.
Corresponding author: Florent Malard     Email:florent.malard@inserm.fr
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Authors
Yishan Ye
Laure Ricard
Lama Siblany
Nicolas Stocker
Frédéric De Vassoigne
Eolia Brissot
Baptiste Lamartheé
Arsène Mekinian
Mohamad Mohty
Béatrice Gaugler
Florent Malard

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