Therapeutic effects of the artemisinin analog SM934 on lupus-prone MRL/lpr mice via inhibition of TLR-triggered B-cell activation and plasma cell formation

Abstract

We previously reported that SM934, a water-soluble artemisinin derivative, was a viable treatment in murine lupus models. In the current study, we further investigated the therapeutic effects of a modified dosage regimen of SM934 on lupus-prone MRL/lpr mice and explored its effects on B cell responses, a central pathogenic event in systemic lupus erythematosus (SLE). When orally administered twice-daily, SM934 significantly prolonged the life-span of MRL/lpr mice, ameliorated the lymphadenopathy symptoms and decreased the levels of serum anti-nuclear antibodies (ANAs) and of the pathogenic cytokines IL-6, IL-10 and IL-21. Furthermore, SM934 treatment restored the B-cell compartment in the spleen of MRL/lpr mice by increasing quiescent B cell numbers, maintaining germinal center B-cell numbers, decreasing activated B cell numbers and reducing plasma cell (PC) numbers. Ex vivo, SM934 suppressed the Toll-like receptor (TLR)-triggered activation and proliferation of B cells, as well as antibody secretion. Moreover, the present study demonstrated that SM934 interfered with the B-cell intrinsic pathway by downregulating TLR7/9 mRNA expression, MyD88 protein expression and NF-kB phosphorylation. In human peripheral blood mononuclear cells (PBMCs), consistent with the results in MRL/lpr mice, SM934 inhibited TLR-associated B-cell activation and PC differentiation. In conclusion, a twice daily dosing regimen of SM934 had therapeutic effects on lupus-prone MRL/lpr mice by suppressing B cell activation and plasma cell formation. Cellular & Molecular Immunology

Toll-like receptors: potential targets for lupus treatment

“…In preclinical study, SM934 exhibited significant protective effects on both MRL/lpr mice and NZBW/F1 mice [84][85][86] . The therapeutic mechanism of SM934 involves inhibiting TLR7/9-triggered B cell activation in a MyD88-dependent way [87] . Since 1956, no new chemical drug for SLE treatment has reached the market in the USA, and no original class I chemical drugs have been developed in China.…”

Hemozoin‐induced activation of human monocytes toward M2‐like phenotype is partially reversed by antimalarial drugs—chloroquine and artemisinin

“…In this regard, we conducted experiments with CHQ and ART for three reasons; first, they are reported to inhibit pathways crucial for polarization to M2 type; second, they are widely used for treatment of malaria; and third, they possess immunomodulatory properties. ART have been reported to decrease IL‐10, IL‐1β, IL‐6, and TNF‐α levels (Shakir, Hussain, Javeed, Ashraf, & Riaz, ; Wu et al., ) through MAPK (Wang et al., ), NF‐κB (Prato, Gallo, Giribaldi, Aldieri, & Arese, ; Wang et al., ), and PI3K‐AKT (Kim et al., ) pathways. CHQ has also been demonstrated to act through MAPK (Kono et al., ; Weber, Chen, & Levitz, ) and NF‐κB(Long, Liu, Wang, Zhou, & Zheng, ; Yang et al., ) pathways and decrease IL‐1β, IL‐6, and TNF‐α in mononuclear phagocytes in different diseases (Jang et al., ; Long et al., ).…”

Immunomodulation of artemisinin and its derivatives

“…In SLE mice, SM934 relieved glomerulonephritis and reduced the production and accumulation of IgG2a and IgG3autoantibodies in serum and renal tissue, suppressed enhancement of effector/memory T-cells, and increased Treg cells counts [43]. More recently, SM934 was found ameliorated the progression of SLE through suppressing the B cells expansion and activation and also blocking plasma cells generation in mice [79].…”