Ab0143 vorinostat improves the pathogenesis of sle model mice by suppressing ifn-i and tlr7/8 signals

Background SLE is a systemic autoimmune disease caused by impaired innate and acquired immune tolerance, resulting in increased Type I IFN (IFN-I) and aberrant B cell development, in which cGAS and TLR 7/8 signaling play critical roles. TLR7/8 and cGAS signal is activated due to the overresponse to nucleic acid derived from impaired clearance of apoptotic cells, which leads to increased IFN-I production. Activation of TLR7/8 signaling also leads to the development of abnormal B cell populations, including short-lived plasma blasts, double negative B cells (DNB), and active native B (NAB). It suggests that signaling pathway via TLR7/8 and cGAS would be a good therapeutic target for SLE. Therefore, we screened agents that inhibit the induction of interferon-stimulated genes (ISGs) by LPS, R848 or cGAMP stimulation using an approved drug library and found that vorinostat inhibits ISG induction upon cGAMP and LPS stimulation. Objectives The purpose of this study is to elucidate the mechanism by which vorinostat suppresses IFN-I production and to demonstrate that vorinostat improves the severity of the disease phenotype in SLE-prone mice. Methods We investigated the effect of vorinostat on the expression and phosphorylation of TBK1, IRF3, IRF5, and IRF7, upon LPS or cGAMP stimulation, as well as on the in vitro differentiation of human B cells into plasma cells by a culture medium containing R848. Additionally, the effect of Vorinostat on the severity of SLE-prone mice, such as NZB/W F1 mice and SAVI mice with point mutations in STING, was also investigated. Results Vorinostat inhibited TBK1 phosphorylation and subsequent nuclear translocation of IRF3 and expression of IRF5 and IRF7. Consequently, the expression of IFN-β and ISGs were suppressed. Additionally, differentiation of human B cells cultured in R848-containing medium into plasma cells was inhibited in the presence of vorinostat. Furthermore, vorinostat improved the disease severity of NZB/W F1 mice, including survival, proteinuria, and glomerulonephritis, and decreased autoantibody titer and TLR7 expression. Vorinostat also ameliorated the lung inflammation and fibrosis, and interstitial nephritis in SAVI mice by inhibiting the ISG expression. Conclusion We found vorinostat ameliorates the disease severity of SLE prone mice by inhibiting IFN-I production and pathogenic B cell development via suppressing the downstream signal of TLR7/8 and cGAS. This finding represents a new therapeutic candidate for SLE. REFERENCES: NIL. Acknowledgements: NIL. Disclosure of Interests None Declared.