Background/Purpose: Patients with Sjögren’s syndrome (SjS) often present with a heightened type I IFN response. Recognition of DNA within the cytosol by a multitude of cytosolic DNA sensors and downstream activation of the stimulator of interferon gene (STING) protein is a key pathway for the induction of type I IFN. So far, only indirect evidence suggests that this pathway might be involved in the pathophysiology of SjS. Thus, the major objective of this study was to investigate the role of STING activation in the etiopathogenesis of SjS.

Methods: Female C57BL/6 mice (10-12 weeks old) were injected with a STING agonist dimethylxanthenone-4-acetic acid (DMXAA) and control mice were treated similarly with the vehicle. Salivary glands were monitored for gene expression by real time PCR and for inflammatory cell infiltration by immunohistochemistry and flow cytometry. Salivary gland function was evaluated by measuring pilocarpine-induced salivation. Sera were analyzed for cytokines and autoantibodies. Cultured primary salivary gland cells were used to study the expression and activation of STING in vitro.

Results: DMXAA treatment rapidly upregulated the expression of Ifnβ and pro-inflammatory cytokines, both systemically and locally in the salivary glands. In the murine submandibular glands, STING expression was detected only in the acinar, but not in the ductal cells. In vitro activation of STING in cultured primary salivary gland cells rapidly phosphorylated TBK1, IRF3 and induced the expression of Ifnβ and TNFα. Within 4 weeks of treatment, in comparison with the vehicle group, DMXAA treated mice developed significantly higher incidence of sialoadenitis (1/17 versus 10/21, p=0.009). The inflammatory cell infiltrates were mainly composed of CD4+T cells and F4/80+ activated macrophages. At early stages of the disease, significantly increased numbers of Lin- NK1.1+: NK cells (CD49b+CD49a-), tissue resident type I innate lymphoid cells (ILC1) (CD49a+CD49b-) and salivary gland ILC1 (CD49a+CD49b+) were observed in the salivary glands. The mean saliva amount in DMXAA treated group (56±14 mg) was significantly lower (p=0.001) than the untreated (80±20 mg) and the vehicle treated groups (78±25). The incidence of high titer ANA (>400) was significantly higher (p=0.02) in the DMXAA group (8/16) than in the vehicle treated group (0/8).

Conclusion: This study demonstrates that activation of STING protein induces certain features of SjS in mice. Our study also suggests that IFN-γ producing ILC1s might be involved in the initial stages of salivary gland disease in SjS. We would like to propose that apart from viral infections, conditions that cause cellular perturbations and accumulation of host DNA within the cytosol should be considered as possible endogenous triggers for SjS.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/activation-of-a-cytosolic-dna-sensor-pathway-in-the-etiopathogenesis-of-sjogrens-syndrome/