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.
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.
Laboratory of Immunopharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
Yanwei
Y
Wu
Laboratory of Immunopharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
Shijun
S
He
Laboratory of Immunology and Virology, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
Bingxin
B
Bai
Laboratory of Immunopharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
Luyao
L
Zhang
Laboratory of Immunology and Virology, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
Lu
L
Xue
Laboratory of Immunology and Virology, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
Zemin
Z
Lin
Laboratory of Immunopharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
Xiaoqian
X
Yang
Laboratory of Immunopharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
Fenghua
F
Zhu
Laboratory of Immunopharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
Peilan
P
He
Laboratory of Immunopharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
Wei
W
Tang
Laboratory of Immunopharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.|Laboratory of Immunology and Virology, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
Jianping
J
Zuo
D000818:Animals; D037621:Artemisinins / Q000494:pharmacology / Q000627:therapeutic use*; D001323:Autoantibodies / Q000097:blood; D002451:Cell Compartmentation / Q000187:drug effects; D016207:Cytokines / Q000097:blood; D018450:Disease Progression; D005260:Female; D006801:Humans; D056724:Immunity, Humoral / Q000187:drug effects; D008181:Lupus Nephritis / Q000097:blood / Q000150:complications / Q000188:drug therapy* / Q000276:immunology*; D000072281:Lymphadenopathy / Q000097:blood / Q000150:complications / Q000276:immunology / Q000473:pathology; D008213:Lymphocyte Activation / Q000187:drug effects*; D019463:Mice, Inbred MRL lpr; D053594:Myeloid Differentiation Factor 88 / Q000378:metabolism; D010950:Plasma Cells / Q000187:drug effects / Q000276:immunology*; D015398:Signal Transduction / Q000187:drug effects; D013154:Spleen / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D013163:Splenomegaly / Q000150:complications / Q000188:drug therapy / Q000276:immunology / Q000473:pathology; D016019:Survival Analysis; D051193:Toll-Like Receptors / Q000819:agonists / Q000378:metabolism*
D037621:Artemisinins; D001323:Autoantibodies; D016207:Cytokines; D053594:Myeloid Differentiation Factor 88; D051193:Toll-Like Receptors; C550182:beta-aminoarteether maleate; C031327:artemisinin