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329 Elevated ifit3 in monocytes contributed to hyperactive cgas-sting signalling pathway in sle
  1. J Wang,
  2. B Qu and
  3. N Shen
  1. Ren Ji Hospital- School of Medicine- Shanghai Jiao Tong University, Rheumatology, Shanghai, China

Abstract

Background and aims IFIT3 is one of the Interferon-stimulated genes showed significantly increase in PBMCs of SLE patients. However, the functions of IFIT3 in dysregulated immune responses of SLE are not fully understood. SLE is featured by over production of nuclear antigens, such as dsDNAs, from debris of numerous dead cells, which give rise to autoantibody production. cGAS-STING signalling pathway has been proposed to play an important role in sensing DNA and producing inflammatory cytokines in SLE. Our study is IFIT3’s function in regulating cGAS-STING signalling pathway in SLE.

Methods Monocytes were isolated from SLE patients or healthy controls by Ficoll-paque method and CD14+ magnetic beads. The expression of IFNβ and phosphorylation of IRF3 were measured in either IFIT3 over-expressing or knockout cells upon VACV-70 stimulation by Q-PCR and Western blot. We used Co-IP to identify the interaction between IFIT3 and its interaction proteins.

Results cGAS-STING signalling pathway was over-activated in monocytes from SLE patients compared to healthy controls. The expression of IFIT3 was significantly elevated in SLE patients and was positively correlated with the activity of cGAS-STING signalling pathway. In vitro, we revealed that the expression of IFNβ and phosphorylation of IRF3 could be reduced by knocking down IFIT3, while over-expression of IFIT3 produced an opposite effect. Mechanistically, IFIT3 protein was found to interact both with STING and TBK1.

Conclusions We proposed that cGAS-STING signalling pathway was hyperactive in monocytes of SLE. IFIT3 is one of the important genes which contributed to the over-activation of cGAS-STING signalling pathway and over-produced IFN in SLE pathogenesis.

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