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

• Published in: Cellular & molecular immunology Vol. 13; no. 3; pp. 379 - 390
• Main Authors: Wu, Yanwei, He, Shijun, Bai, Bingxin, Zhang, Luyao, Xue, Lu, Lin, Zemin, Yang, Xiaoqian, Zhu, Fenghua, He, Peilan, Tang, Wei, Zuo, Jianping
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.05.2016; Nature Publishing Group
• Subjects: Animal models; Animals; Antibodies; Artemisinin; Artemisinins - pharmacology; Artemisinins - therapeutic use; Autoantibodies - blood; Biomedical and Life Sciences; Biomedicine; Cell activation; Cell Compartmentation - drug effects; Cell differentiation; Cell proliferation; Cytokines - blood; Disease Progression; Female; Gene expression; Humans; Immunity, Humoral - drug effects; Immunology; Interleukin 10; Interleukin 21; Interleukin 6; Leukocytes (mononuclear); Lupus; Lupus Nephritis - blood; Lupus Nephritis - complications; Lupus Nephritis - drug therapy; Lupus Nephritis - immunology; Lymphadenopathy; Lymphadenopathy - blood; Lymphadenopathy - complications; Lymphadenopathy - immunology; Lymphadenopathy - pathology; Lymphocyte Activation - drug effects; Lymphocytes B; Medical Microbiology; Mice, Inbred MRL lpr; Microbiology; MyD88 protein; Myeloid Differentiation Factor 88 - metabolism; NF-κB protein; Oral administration; Peripheral blood mononuclear cells; Phosphorylation; Plasma Cells - drug effects; Plasma Cells - immunology; research-article; Signal Transduction - drug effects; Spleen - drug effects; Spleen - metabolism; Spleen - pathology; Splenomegaly - complications; Splenomegaly - drug therapy; Splenomegaly - immunology; Splenomegaly - pathology; Survival Analysis; Systemic lupus erythematosus; TLR7 protein; Toll-like receptors; Toll-Like Receptors - agonists; Toll-Like Receptors - metabolism; Vaccine; B cell; systemic lupus erythematosus; SM934; plasma cell; Toll-like receptor
• ISSN: 1672-7681; 2042-0226
• DOI: 10.1038/cmi.2015.13

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-κB 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.