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.

We have previously reported that organ cultured coronary arteries from market-age pigs (6-9 months of age) exhibit an enhanced contraction to the atherosclerotic-associated peptide, endothelin-1 (ET-1). The objective of this study was to investigate the interaction of 17β-estradiol with ET-1 in organ cultured coronary arteries from older female pigs (3-4 years old). A cumulative-concentration response relationship (1 × 10 −9 M to 3 × 10 −7 M) was generated to ET-1, and the isometric tension measured in fresh and organ cultured (4 days at 37°C) arterial rings that were each pre-incubated for 50 minutes in different concentrations (1 × 10 −9 M to 1 × 10 −5 M) of 17β-estradiol. Compared to freshly used arteries, culturing induced a 2-fold increase in tension development to ET-1 (3 × 10 −7 M). Although 17β-estradiol previously relaxed pre-constricted (with a 60 mM KCl solution) arteries, it did not affect the constrictive response to ET-1. Also, using an ET-1 ELISA we found that 17β-estradiol did not effect ET-1 production in intact arteries. Our results indicate that 17β-estradiol does not attenuate the production and constrictive properties of ET-1 in coronary arteries demonstrating a dedifferentiated cell phenotype.

Changes made in the 8th edition of the Guide for the Care and Use of Laboratory Animals included new recommendations for the amount of space for breeding female mice. Adopting the new recommendations required, in essence, the elimination of trio breeding practices for all institutions. Both public opinion and published data did not readily support the new recommendations. In response, the National Jewish Health Institutional Animal Care and Use Committee established a program to directly compare the effects of breeding format on mouse pup survival and growth. Our study showed an overall parity between trio and pairwise breeding formats on the survival and growth of the litters, suggesting that the housing recommendations for breeding female mice as stated in the current Guide for the Care and Use of Laboratory Animals should be reconsidered.

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.