Exploring cGAS-STING Pathway in Sjögren’s Disease: Driver of IFN production and Potential Therapeutic Target

Abstract Sjögren's Disease (SjD) is a prevalent autoimmune disorder characterized by dysfunctional lacrimal and salivary glands (SG) and lacks an effective therapy. Despite unknown pathogenic mechanisms, elevated interferon (IFN) expression is observed in SjD patients. Recent findings indicate activation of the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway in systemic lupus, prompting investigation into its role in SjD. We hypothesize cGAS-STING pathway activation in SjD contributing IFN dysregulation and symptoms. Bulk and single-cell RNA sequencing of SjD SG shows elevated IFN-related genes in epithelial and inflammatory cells. Investigation of the affected human SG by flow cytometry confirms upregulated phosphorylation status of cGAS-STING proteins in epithelial and immune cells; and epithelial cGAS-STING pathway activation directly correlates with the level of immune cell infiltration. Treatment of patient’s SG and peripheral blood mononuclear cells (PBMC) with a STING antagonist ex vivo reduces phosphorylated protein levels without cytotoxicity. These findings support our hypothesis that targeting the cGAS-STING pathway holds promise for mitigating salivary gland inflammation in SjD, preventing chronic inflammation's secondary effects and resulting tissue destruction.