Arsenic trioxide improves Treg and Th17 balance by modulating STAT3 in treatment-naïve rheumatoid arthritis patients

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.

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.

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.

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.