Department of Translational Medicine, The First Hospital of Jilin University, Changchun, 130021, China.
Department of Rheumatology and Immunology, The First Hospital of Jilin University, Changchun, 130021, China.
J Autoimmun. 2022 Oct;132:102894. doi: 10.1016/j.jaut.2022.102894. Epub 2022 Aug 26.
Lupus nephritis (LN) is the most common cause of morbidity and mortality in patients with systemic lupus erythematosus (SLE). Currently, immunosuppressive treatments for LN are suboptimal and can induce significant side effects. SB431542 is a selective and potent inhibitor of the TGFβ/Activin/NODAL pathway. Here, we study the effects of SB431542 treatment on LN and discuss the potential mechanisms. SB431542 ameliorated clinical outcomes with a consequent histological improvement in NZB/W mice. A comparative transcriptional profiling analysis revealed 586 differentially expressed genes (247 downregulated genes) in the SB431542 group compared to the control group. We found that the downregulated genes were mainly enriched in the biological processes of B cell activation, B cell proliferation, B cell differentiation, and B cell receptor signaling. Kyoto encyclopedia of genes and genomes pathway analysis revealed that the hematopoietic cell linage pathway was significantly downregulated in the SB431542 group. In addition, we observed that SB431542 reduced the splenic or renal levels of CD20 and the serum levels of anti-dsDNA antibody (IgG) in NZB/W mice. Furthermore, qRT-PCR and immunohistochemistry confirmed that SB431542 inhibits the production of TLR9, TGFβ1, and PDGFB. Thus, due to its immunomodulatory activities, SB431542 could be considered for clinical therapy development for LN.
狼疮肾炎 (LN) 是系统性红斑狼疮 (SLE) 患者发病和死亡的最主要原因。目前，LN 的免疫抑制治疗效果并不理想，且会引发严重的副作用。SB431542 是一种 TGFβ/Activin/NODAL 通路的高选择性、高效抑制剂。本研究旨在探讨 SB431542 治疗 LN 的作用机制。结果表明，SB431542 改善了 NZB/W 小鼠的临床结局，并伴有组织学改善。比较转录组分析显示，与对照组相比，SB431542 组有 586 个差异表达基因（247 个下调基因）。我们发现，下调基因主要富集在 B 细胞激活、B 细胞增殖、B 细胞分化和 B 细胞受体信号等生物学过程中。京都基因与基因组百科全书通路分析显示，SB431542 组造血细胞谱系通路显著下调。此外，我们观察到 SB431542 降低了 NZB/W 小鼠脾脏或肾脏中的 CD20 水平和血清中抗 dsDNA 抗体 (IgG)的水平。实时定量 PCR 和免疫组织化学进一步证实，SB431542 抑制 TLR9、TGFβ1 和 PDGFB 的产生。综上，SB431542 具有免疫调节活性，可考虑用于 LN 的临床治疗开发。
