Background/Purpose: Interferona (IFNa) is increased and plays an important role in the pathogenesis of systemic lupus erythematosus (SLE). Overexpression of type I IFN regulated genes has been reported in patients with SLE. Plasmacytoid dendritic cells (pDCs) are thought as the main producer of IFNa upon activation of TLR pathway. However, IFNa producers by the stimulation of cyclic GMP-AMP synthase (cGAS) and stimulator of interferon genes (STING) in SLE still remains unknown. In this study, we investigated the IFNa producing capacity of myeloid cells under stimulation of cGAS-STING pathway.

Methods: Peripheral blood mononuclear cells from patients with SLE and healthy controls were stimulated with 2’3’c-GAMP, a stimulator of cGAS-STING pathway, or a TLR-7 agonist, imiquimod, and IFNa-producing capacity of myeloid cells was examined by intracellular cytokine staining and flow cytometry. The expression and co-localization of STING with TBK1 were examined by intracellular staining and flow cytometry or confocal microscopy. The effect of in vitro IFNa exposure on IFNa production and STING expression was examined. Monocytes were treated with rapamycin in vitro, and IFNa production and the expression of STING, pTBK1, IRF3 were examined.

Results: As previously reported, IFNa was produced from only pDCs upon activation of TLR7 pathway. However, IFNa was produced from monocytes, conventional dendritic cells (cDCs) and pDCs upon activation of cGAS-STING pathway. The frequency of IFNa-producing monocytes stimulated with 2’3’c-GAMP positively correlated with disease activity of SLE. The expression of STING and its co-localization with TBK1 were increased in lupus monocytes. Prior exposure to IFNa enhanced the IFNa-producing capacity of monocytes. Inhibition of mechanistic target of rapamycin (mTOR) pathway by using rapamycin suppressed IFNa production from monocytes and downregulated the enhanced expression of STING pathway.

Conclusion: We demonstrate that lupus monocytes are potent to produce IFNa in association with the augmentation of cGAS-STING pathway. Production of IFNa and enhancement of cGAS-STING pathway was suppressed by the inhibition of mTOR pathway. These findings indicate that enhanced IFNa from lupus monocytes owing to augmented STING pathway is associated with the pathogenesis of SLE. The blockade of the cGAS-STING pathway may serve as a promising therapeutic target for SLE.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/enhanced-ifn-a-production-and-sting-pathway-in-monocytes-in-systemic-lupus-erythematosus-is-suppressed-by-the-inhibition-of-mtor-activation/