Niclosamide Suppresses the Expansion of Follicular Helper T Cells and Alleviates Disease Severity in Two Murine Models of Lupus Via STAT3
Journal of translational medicine(2021)
摘要
Background Autoantibody production against endogenous cellular components is pathogenic feature of systemic lupus erythematosus (SLE). Follicular helper T (T FH ) cells aid in B cell differentiation into autoantibody-producing plasma cells (PCs). The IL-6 and IL-21 cytokine-mediated STAT3 signaling are crucial for the differentiation to T FH cells. Niclosamide is an anti-helminthic drug used to treat parasitic infections but also exhibits a therapeutic effect on autoimmune diseases due to its potential immune regulatory effects. In this study, we examined whether niclosamide treatment could relieve lupus-like autoimmunity by modulating the differentiation of T FH cells in two murine models of lupus. Methods 10-week-old MRL/ lpr mice were orally administered with 100 mg/kg of niclosamide or with 0.5% methylcellulose (MC, vehicle) daily for 7 weeks. TLR7 agonist, resiquimod was topically applied to an ear of 8-week-old C57BL/6 mice 3 times a week for 5 weeks. And they were orally administered with 100 mg/kg of niclosamide or with 0.5% MC daily for 5 weeks. Every mouse was analyzed for lupus nephritis, proteinuria, autoantibodies, immune complex, immune cell subsets at the time of the euthanization. Results Niclosamide treatment greatly improved proteinuria, anti-dsDNA antibody levels, immunoglobulin subclass titers, histology of lupus nephritis, and C3 deposition in MRL/ lpr and R848-induced mice. In addition, niclosamide inhibited the proportion of T FH cells and PCs in the spleens of these animals, and effectively suppressed differentiation of T FH -like cells and expression of associated genes in vitro. Conclusions Niclosamide exerted therapeutic effects on murine lupus models by suppressing T FH cells and plasma cells through STAT3 inhibition.
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关键词
Systemic lupus erythematosus,MRL/lpr,R848-induced model,Niclosamide,STAT3,Follicular helper T cells
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