SB431542 alleviates lupus nephritis by regulating B cells and inhibiting the TLR9/TGFβ1/PDGFB signaling

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.