68 Administration of artemisinin analogue SM934 ameliorates disease manifestation in lupus-prone mice via restoring immune homeostasis

Abstract

Background Artemisinin and its derivatives were reported to possess strong regulatory effects on inflammation and autoimmune diseases. This study was designed to examine the therapeutic effects and underlying mechanisms of SM934, a water-soluble artemisinin analogue, on lupus-prone mice. Methods For MRL/lpr mice: In vivo, the preventative or therapeutic effects of SM934 in MRL/lpr mice were investigated. Ex vivo, the mechanisms of treatment were explored according to the immunologic correlates of disease. Impacts of SM934 on Toll-like receptor (TLR)-triggered B cell responses were evaluated. In vitro, the effects of SM934 on the activation and differentiation of CD4 +T cells were examined. For NZB/W F1 mice: In vivo, the lupus-prone mice were treated with SM934 for 3 or 6 months respectively to investigate the effect on clinical manifestations and immunological correlates. To further explore the mechanisms of SM934, ovalbumin (OVA)-immunized or interferon (IFN)--elicited C57BL/6 mice were used. Results In vivo, SM934 treatment significantly prolonged the life-span of MRL/lpr mice, ameliorated the lymphadenopathy, decreased the levels of serum anti-nuclear antibodies (ANAs) and the pathogenic cytokines IFN-, IL-6, IL-10 and IL-21, and reduced the proportion of double negative T cells. Treatment with SM934 significantly delayed the progression of glomerulonephritis and improved the survival of NZB/W F1 mice. Clinical improvement was accompanied with decreased anti-dsDNA Abs and serum interleukin IL-17. In addition, SM934 treatment promoted the IL-10 production from macrophages of NZB/W F1 mice, OVA-immunized C57BL/6 mice and IFN--elicited C57BL/6 mice. Ex vivo, SM934 treatment elevated the percentage of Treg cells, inhibited the development of Th1 and Th17 cells. Moreover, SM934 suppressed the TLR-triggered activation and proliferation of B cells. In vitro, SM934 inhibited the differentiation of Th1 and Th17 cells as well as TLR-associated B-cell activation and plasma cell differentiation. SM934 enhanced IL-10 production from primary macrophages stimulated with IFN-. Conclusions Taken together, these results demonstrated that the artemisinin analogue SM934 exerted significant therapeutic benefits in lupus-prone mice, by inhibiting both the pathogenic helper T cell development and responses, enhancing anti-inflammatory cytokine IL-10 production and suppressing plasma cell formation. These properties of SM934 might contributed to the restoration of the immune homeostasis in lupus-susceptible mice, and thus cast a light on a novel strategy for lupus treatment. Funding Source(s): National Science Fair Committee (NSFC), China (No. 81273524, 81322049), National Science and Technology Major Project New Drug Creation and Manufacturing Program, China (2014Z × 09101002) and National Key Basic Research Programme (973 Programme, 2014CB541906). Artemisinin analogue SM934 treatment restore immune homeostasis in lupus-prone mice