Activation of the Stimulator of Interferon Gene Protein is Involved in the Etiopathogenesis of Sjogren’s Syndrome

Abstract

Abstract Activation of innate immune responses and excessive production of type I Interferons (IFNs) plays a critical role in the pathogenesis of Sjögren’s syndrome (SS), a chronic autoimmune disorder affecting the exocrine salivary glands (SG). Recognition of nucleic acids by cytosolic nucleic acid sensors is a major trigger for type I IFN production. Several cytosolic DNA sensors interact downstream with the stimulator of interferon gene (STING) protein and induce type I IFNs. Although STING has been implicated in several interferonopathies, its role in SS is not known. To investigate whether STING activation is involved in the etiopathogenesis of SS, in this study, female C57BL/6 mice were injected with a STING agonist, dimethylxanthenone-4-acetic acid (DMXAA) and mice were followed for the development of SS. Systemic DMXAA treatment rapidly induced the expression of Ifnb1, Il6, and Tnfa in the SG, and these cytokines were also elevated in circulation. In contrast, increased Ifng gene expression was only detected in the SGs. The type I innate lymphoid cells present within the SG were the major source of IFNγ, and their numbers increased significantly within 3 days of DMXAA treatment. STING expression in SG was mainly observed in the ductal and interstitial cells. In primary SG cells, DMXAA activated STING, which caused phosphorylation of TBK1 and IRF3, and induced IFN-β production. The DMXAA-treated mice developed autoantibodies, sialoadenitis, and SG hypofunction. Our study demonstrates that activation of STING pathway holds the potential to initiate SS. Thus, apart from viral infections, conditions that cause cellular perturbations and accumulation of host DNA within the cytosol should also be considered as possible triggers for SS.