Association of Abnormal Elevations in IFIT3 With Overactive Cyclic GMP‐AMP Synthase/Stimulator of Interferon Genes Signaling in Human Systemic Lupus Erythematosus Monocytes

Objective Increasing evidence indicates that the cyclic GMP ‐ AMP synthase/stimulator of interferon genes ( cGAS / STING ) signaling pathway has a critical pathogenic role in systemic lupus erythematosus ( SLE ). Expression levels of the interferon (IFN)–inducible gene IFIT 3 are elevated in SLE patients. However, it is still not clear how IFIT 3 contributes to the pathogenesis of SLE . This study was undertaken to investigate the activation of the cGAS / STING signaling pathway in human SLE monocytes, and to determine how elevated expression of IFIT 3 could contribute to overactive cGAS / STING signaling in patients with SLE. Methods Monocytes from SLE patients or healthy controls were examined for activity of the cGAS / STING signaling pathway and expression levels of IFIT 3. Correlations between cGAS / STING signaling activity and SLE clinical features were analyzed. Gain‐ or loss‐of‐function experiments were used to determine the role of IFIT 3 in cGAS / STING signaling. Coimmunoprecipitation assays were used to identify the interaction between IFIT 3 and other proteins. Results The cGAS / STING signaling pathway was found to have enhanced activity in monocytes from SLE patients compared to healthy controls, as indicated by the higher expression of IFN β downstream. Levels of IFIT 3 were significantly elevated in human SLE monocytes, and this was positively correlated with the activity of the cGAS / STING signaling pathway. In vitro, the expression of VACV 70‐induced IFN β was reduced by knockdown of IFIT 3, whereas overexpression of IFIT 3 produced an opposite effect. Finally, IFIT 3 was found to interact with both STING and TANK ‐binding kinase 1. Conclusion These findings suggest that IFIT 3 is one of the genes that contributes to the overactive cGAS / STING signaling pathway in human SLE monocytes. IFIT 3 may therefore serve as a novel therapeutic target for blocking the production of type I IFN and other proinflammatory cytokines by the cGAS / STING signaling pathway in patients with SLE.