Abnormal Overactive CGAS-STING Signaling In Human Systemic Lupus Erythematosus Monocytes

Objective:Increasing evidence indicate a critical pathogenic role of cGAS-STING signaling pathway in systemic lupus erythematosus.Interferon inducible gene,IFIT3,is elevated in systemic lupus erythematosus.However,it is still not clear how IFIT3 contributes to systemic lupus erythematosus pathogenesis.We undertook this study to investigate the activation of cGAS-STING signaling pathway in systemic lupus erythematosus monocytes,as well as how elevated IFIT3 contributes to the overactivation of cGAS-STING signaling pathway.Methods and Materials:1.Monocytes from systemic lupus erythematosus patients or healthy controls were examined for the activity of cGAS-STING signaling pathway as indicated by VACV70-induced IFN?.We also analyzed the association between cGAS-STING signaling pathway activity and systemic lupus erythematosus clinical features;2.qPCR was used to detect the mRNA expression of IFIT3,and analyze the correlation between cGAS-STING signaling activity and IFIT3 expression;3.Gain or loss of function experiments were used to determine the role of IFIT3 in cGAS-STING signaling pathway;4.Co-IP and Western Blot were used to identify the interaction between IFIT3 and other proteins.Results:1.cGAS-STING signaling pathway had enhanced activity in monocytes from systemic lupus erythematosus patients compared to healthy controls,and activation of cGAS-STING signaling pathway was higher in active systemic lupus erythematosus patients;2.The expression of IFIT3 was significantly elevated in systemic lupus erythematosus patients and was positively correlated with the activity of cGAS-STING signaling pathway;3.In vitro,we found that the expression of VACV70-induced IFN? could be reduced by knocking down IFIT3,while over-expression of IFIT3 produced an opposite effect;4.Mechanistically,IFIT3 was found to interact with both STING and TBK1,and IFIT3 functioned as an adaptor for the binding of TBK1 to STING.Conclusion:We propose that IFIT3 is one of the genes which contribute to the overactive cGAS-STING signaling pathway in systemic lupus erythematosus monocytes,which may serve as a therapeutic target to block the production of type I IFN and other pro-inflammatory cytokines by cGAS-STING signaling pathway.