Chunling Li1, Juan Zhang1, Weiyan Wang1, Hui Wang1, Yue Zhang2, Zhiyi Zhang3. 1. Department of Rheumatology, The First Affiliated Hospital of Harbin Medical University, 23 Youzheng St., Nangang District, Harbin, China. 2. Department of Rheumatology, The First Affiliated Hospital of Harbin Medical University, 23 Youzheng St., Nangang District, Harbin, China; Shenzhen Futian Hospital for Rheumatic Diseases, 22 Nonglin Road, Shenzhen, China. Electronic address: toronto101@163.com. 3. Department of Rheumatology, The First Affiliated Hospital of Harbin Medical University, 23 Youzheng St., Nangang District, Harbin, China. Electronic address: zhangzhiyi2014@163.com.
Abstract
OBJECTIVE: We aimed to investigate the immunologic mechanisms by which arsenic trioxide (As2O3) may inhibit T helper 17 (Th17) cell differentiation while promoting regulatory T (Treg) cell generation by modulating signal transducer and activator of transcription 3 (STAT3) in treatment-naïve rheumatoid arthritis (RA) patients. METHODS: Naïve CD4+T cells isolated by fluorescence-activated cell sorting from treatment-naïve RA patients and healthy controls were used to investigate the effect of As2O3 on the process of polarization and the related cytokines. STAT3 transfection experiments were conducted with small interfering RNA (siRNA) and lentivirus STAT3 to verify the mechanism of As2O3 on Th17-Treg balance in vitro. A collagen-induced arthritis (CIA) model was used to detect the clinical scores, histopathological change, bone destruction, Th17-Treg proportion and joint tissue immunohistochemistry. RESULTS: We found that As2O3 prevented activated naïve CD4+T-cells from differentiating into Th17 cells and reduced cytokine production by activated Th17 cells by downregulating their signature transcription factors, STAT3 and orphan nuclear receptors. Notably, As2O3 reduced Th17 cells frequency while increasing Treg cells frequency under specific polarizing conditions in treatment-naïve RA patients by transfecting siRNA STAT3 and lentivirus STAT3. Furthermore, we noticed that applying As2O3 in the CIA model attenuated the infiltration of joint inflammation and bone destruction, and significantly improved the imbalanced Treg-Th17 ratio. CONCLUSIONS: These data indicate that As2O3 may be a potential immune modulator for treatment-naïve RA patients that helps to balance of Treg and Th17 cells through modulating STAT3.
OBJECTIVE: We aimed to investigate the immunologic mechanisms by which arsenic trioxide (As2O3) may inhibit T helper 17 (Th17) cell differentiation while promoting regulatory T (Treg) cell generation by modulating signal transducer and activator of transcription 3 (STAT3) in treatment-naïve rheumatoid arthritis (RA) patients. METHODS: Naïve CD4+T cells isolated by fluorescence-activated cell sorting from treatment-naïve RApatients and healthy controls were used to investigate the effect of As2O3 on the process of polarization and the related cytokines. STAT3 transfection experiments were conducted with small interfering RNA (siRNA) and lentivirus STAT3 to verify the mechanism of As2O3 on Th17-Treg balance in vitro. A collagen-induced arthritis (CIA) model was used to detect the clinical scores, histopathological change, bone destruction, Th17-Treg proportion and joint tissue immunohistochemistry. RESULTS: We found that As2O3 prevented activated naïve CD4+T-cells from differentiating into Th17 cells and reduced cytokine production by activated Th17 cells by downregulating their signature transcription factors, STAT3 and orphan nuclear receptors. Notably, As2O3 reduced Th17 cells frequency while increasing Treg cells frequency under specific polarizing conditions in treatment-naïve RApatients by transfecting siRNA STAT3 and lentivirus STAT3. Furthermore, we noticed that applying As2O3 in the CIA model attenuated the infiltration of joint inflammation and bone destruction, and significantly improved the imbalanced Treg-Th17 ratio. CONCLUSIONS: These data indicate that As2O3 may be a potential immune modulator for treatment-naïve RApatients that helps to balance of Treg and Th17 cells through modulating STAT3.
Keywords:
Arsenic trioxide; Rheumatoid arthritis; Signal transducer and activator of transcription 3 (STAT3); T helper 17 cells (Th17); T regulatory cells (Treg)
Authors: Mohamed Hamidou; Antoine Néel; Joel Poupon; Zahir Amoura; Mikael Ebbo; Jean Sibilia; Jean-Francois Viallard; Benjamin Gaborit; Christelle Volteau; Jean Benoit Hardouin; Eric Hachulla; François Rieger Journal: Arthritis Res Ther Date: 2021-03-03 Impact factor: 5.156