Arsenic trioxide induces regulatory functions of plasmacytoid dendritic cells through interferon- inhibition.
10.1016/j.apsb.2020.01.016
- Author:
Yishan YE
1
;
Laure RICARD
1
;
Lama SIBLANY
1
;
Nicolas STOCKER
1
;
Frédéric DE VASSOIGNE
2
;
Eolia BRISSOT
1
;
Baptiste LAMARTHÉE
1
;
Arsène MEKINIAN
1
;
Mohamad MOHTY
1
;
Béatrice GAUGLER
1
;
Florent MALARD
1
Author Information
1. Sorbonne Université, INSERM, Centre de Recherche Saint-Antoine (CRSA), Paris F-75012, France.
2. AP-HP, Hôpital Saint-Antoine, Service d'Hématologie Clinique et Thérapie Cellulaire, Paris F-75012, France.
- Publication Type:Journal Article
- Keywords:
Arsenic trioxide;
IFN-I;
Immunotherapy;
Plasmacytoid dendritic cell;
Systemic sclerosis
- From:
Acta Pharmaceutica Sinica B
2020;10(6):1061-1072
- CountryChina
- Language:English
-
Abstract:
Arsenic trioxide (AsO) 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 AsO induced apoptosis of pDCs mitochondrial pathway with increased BAX/BCL-2 ratio, while independent of reactive oxygen species generation. Notably, at clinical relevant concentrations, AsO preferentially inhibited IFN- secretion as compared to other cytokines such as TNF-, 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, AsO 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- inhibition, and regulatory phenotype induced by AsO. Collectively, our data suggest that AsO could target pDCs and exert its treatment efficacy in SSc, and more autoimmune disorders with IFN-I signature.
