Sjögren syndrome (SS), a chronic autoimmune disorder causing dry mouth, 
adversely affects the overall oral health in patients. Activation of innate 
immune responses and excessive production of type I interferons (IFNs) play a 
critical role in the pathogenesis of this disorder. Recognition of nucleic acids 
by cytosolic nucleic acid sensors is a major trigger for the induction of type I 
IFNs. Upon activation, cytosolic DNA sensors can interact with the stimulator of 
interferon genes (STING) protein, and activation of STING causes increased 
expression of type I IFNs. The role of STING activation in SS is not known. In 
this study, to investigate whether the cytosolic DNA sensing pathway influences 
SS development, female C57BL/6 mice were injected with a STING agonist, 
dimethylxanthenone-4-acetic acid (DMXAA). Salivary glands (SGs) were studied for 
gene expression and inflammatory cell infiltration. SG function was evaluated by 
measuring pilocarpine-induced salivation. Sera were analyzed for cytokines and 
autoantibodies. Primary SG cells were used to study the expression and 
activation of STING. Our data show that systemic DMXAA treatment rapidly induced 
the expression of Ifnb1, Il6, and Tnfa in the SGs, and these cytokines were also 
elevated in circulation. In contrast, increased Ifng gene expression was 
dominantly detected in the SGs. The type I innate lymphoid cells present within 
the SGs were the major source of IFN-γ, and their numbers increased 
significantly within 3 d of treatment. STING expression in SGs was mainly 
observed in ductal and interstitial cells. In primary SG cells, DMXAA activated 
STING and induced IFN-β production. The DMXAA-treated mice developed 
autoantibodies, sialoadenitis, and glandular hypofunction. Our study 
demonstrates that activation of the 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.