Therapeutic effects of artesunate on lupus-prone MRL/lpr mice are dependent on T follicular helper cell differentiation and activation of JAK2-STAT3 signaling pathway.

Anti-malarial drug artesunate (ART), a semi-synthetic derivative of artemisnin, has immunosuppressive effects on several autoimmune diseases, including Systemic lupus erythematosus (SLE), Rheumatoid arthritis (RA), and Colitis. However, molecular mechanisms of ART, especially on follicular helper T cells (Tfh), central players in SLE pathology, are far from clear. The object for this work is to investigate the therapeutic effect of ART on lupus-prone MRL/lpr mice and its regulatory function on Tfh cells. MRL/lpr mice were used to explore therapeutic effects of ART on lupus-prone MRL/lpr mice and its regulatory functions on Tfh cells. Then, experiments of renal function were accomplished using the biochemical kits. Effects of ART on histopathology of kidneys, inflammatory factors and autoantibodies were examined using H&E staining, ELISA and real-time PCR. Flow cytometry and western blot analysis were used to examine effects of ART on Tfh differentiation and Jak2-Stat3 signaling pathway. Upon oral administration, ART significantly prolonged the survival of MRL/lpr mice, ameliorated the lupus nephritis symptoms, decreased the levels of anti-dsDNA antibodies deposited in the kidney, and the levels of pathogenic cytokines (IL-6, IFN-γ and IL-21). After ART treatment, T-cell compartment in the spleen of MRL/lpr mice was restored in terms of reduction in the number of Tfh cells and in the maintenance of the ratio of Tfr to follicular regulatory T cells (Tfh). In addition, ART has significantly inhibited the phosphorylation levels of Jak2 and Stat3 in the MRL/lpr mice. ART showed therapeutic effects on lupus-prone MRL/lpr mice by inhibiting the differentiation of Tfh cells as well as altering the activation status of Jak2-Stat3 signaling cascade.

Dang WZ ，Li H ，Jiang B ，Nandakumar KS ，Liu KF ，Liu LX ，Yu XC ，Tan HJ ，Zhou C ... -  《-》

Toll-like receptor 7 agonist imiquimod prevents the progression of SLE in MRL/lpr mice via inhibiting the differentiation of T follicular helper cells.

Previous research has recently indicated that TLR7 is able to induce CD4+T cell anergy, which is the opposite of the role it plays in innate immune cells. Therefore, TLR7 ligands may be used as a manner in which to induce CD4+T cells "tolerance" in autoimmune diseases. T follicular helper (Tfh) cells were demonstrated to be a subset of CD4+T cells that help B cells produce antibodies. The abnormal activity of Tfh cells, though, is their function as a primary pathogenic factor in systemic lupus erythematosus (SLE). However, the role of TLR7 in Tfh cells is not clear. Our study was aimed at determining the influence of TLR7 on Tfh cells in a murine model of SLE (MRL/lpr mice). We were surprised to find that the frequency of Tfh cells and germinal center (GC) B cells was significantly reduced after treatment with the TLR7 agonist imiquimod. Imiquimod also significantly reduced the expression of inducible costimulatory molecule (ICOS) and programmed death 1(PD-1) in Tfh cells and decreased IL-21 secretion. Moreover, imiquimod significantly reduced the mRNA expression of several transcription factors, including Bcl-6, c-Maf, Batf3, Nfatc2 and Stat3, and enhanced the expression of Prdm1 and Stat5b in CD4+T cells. Imiquimod also ameliorated the progression of SLE in MRL/lpr mice by inhibiting anti-dsDNA antibodies and antinuclear antibody (ANA) secretion in the serum. Our findings indicated that TLR7 inhibited the development of Tfh cells both in vivo and ex vivo, which depended on many transcription factors aside from Bcl-6. Our results demonstrated that a TLR7 agonist has the potential to be used to inhibit Tfh cell responses during SLE.

Duan X ，Shen C ，Zhang X ，Wu L ，Chen J ，Ma B ，Wang Q ，Sun P ，Lan Y ，Su C ... -  《-》

T follicular helper cells mediate expansion of regulatory B cells via IL-21 in Lupus-prone MRL/lpr mice.

Yang X ，Yang J ，Chu Y ，Wang J ，Guan M ，Zhu X ，Xue Y ，Zou H ... -  《-》

Niclosamide suppresses the expansion of follicular helper T cells and alleviates disease severity in two murine models of lupus via STAT3.

Jang SG ，Lee J ，Hong SM ，Song YS ，Kim MJ ，Kwok SK ，Cho ML ，Park SH ... -  《-》

Interleukin-9 Is Associated with Elevated Anti-Double-Stranded DNA Antibodies in Lupus-Prone Mice.

Yang J ，Li Q ，Yang X ，Li M ... -  《-》