Artesunate influences Th17/Treg lymphocyte balance by modulating Treg apoptosis and Th17 proliferation in a murine model of rheumatoid arthritis

Abstract

CD4+ regulatory T (Treg) cells and T-helper 17 (Th17) cells have been shown to have important roles in rheumatoid arthritis (RA). In our previous study, it was demonstrated that artesunate was able to alter the Treg/Th17 ratio in patients with RA; however, the underlying mechanisms remain unclear. The present study established a male Sprague Dawley (SD) rat model of type II collagen-induced arthritis (CIA). SD rats were divided into normal control, CIA model and artesunate-treated (5, 10 or 20 mg/kg/day) groups. Treg and Th17 cells were detected in the synovium by immunohistochemical analysis of forkhead/winged helix transcription factor (Foxp3) and interleukin (IL)-17 expression. Subsequently, lymphocytes were extracted from the rat spleens, and the proportions of Treg/Th17 cells were detected by flow cytometry. The results demonstrated that the expression levels of Foxp3 were significantly decreased, and those of IL-17 were significantly increased, in the CIA model group, as compared with the normal control group. The results demonstrated that artesunate decreased the frequency of Th17 cells and increased the frequency of Treg cells in CIA rats in a dose-dependent manner. In conclusion, the present study suggested that artesunate may regulate the Th17/Treg balance by inducing Th17-mediated apoptosis. Therefore, artesunate may be considered a novel therapeutic agent for the treatment of patients with RA.

DataSheet_1.doc

“…In the present study, we have confirmed results of some previous studies showing INCREASED Th17 cells frequency, as well as Th17/Treg ratio in RA patients (16)(17)(18)(19)(20)(21)(22). In contrast to our study, Penatti A et al (23) have shown that RA patients had lower frequencies of circulating CCR6+CXCR3−Th17 cells and higher frequencies of conventional CD25+ Tregs comparing to the OA patients.…”

Immunoregulation by Artemisinin and Its Derivatives: A New Role for Old Antimalarial Drugs

“…Accumulating evidence based on animal models has pointed to the efficacy of ARTs in RA treatment. In type II collagen-induced arthritis (CIA) in rats, artesunate treatment not only alleviated inflammation, decreased the frequency of Th17 cells and increased Treg cells in the synovium and spleen ( 17 ), but also stimulated apoptosis or autophagy in cartilage tissue and inhibited chondrocyte proliferation through the PI3K/AKT/mTOR signaling pathway ( 18 ). Moreover, artesunate exerted a suppressive effect on osteoclastogenesis and improved arthritic bone erosion in CIA rats via inhibiting the production of ROS and activating antioxidant enzyme as well as p62/Nrf2 signaling ( 19 ).…”

Recent pharmacological advances in the repurposing of artemisinin drugs

“…Artemisinin significantly potentiated apoptosis and impaired ROS production in inflammatory‐related diseases 65 . Studies have revealed that artesunate and DC32, a dihydroartemisinin derivative, could reduce footpad swelling and lymphocytic infiltration in collagen‐induced arthritis (CIA) mice by restoring the balance of Treg/T‐helper 17 (Th17) and inhibiting the expression of IL‐6 or IL‐17 66,67 . Besides this, DC32 could significantly activate the Nrf2/HO‐1 signaling pathway and induce p62 transcription in CIA mice 68 .…”