AT-RvD1 Reverses Pro-inflammatory Cytokine Upregulation in Female NOD/ShiLtJ Mouse SMG

Objectives: Sjögren’s Syndrome (SS) is an autoimmune disease affecting approximately 1% of the general population with women accounting for more than 90% of diagnosed cases. The diminished function of the salivary glands is associated with gingivitis, caries, periodontitis and candidiasis, while more advanced complications include infection of the parotid gland, emergence of parotid tumors and lymphomas. Together, these issues impose significant physical, psychological and economic burdens on patients with SS. Although extensive investigation has been done to understand SS, the causes of the disease are still unknown and treatments remain largely ineffective. The goal of this study was to determine if systemic treatment with Aspirin-triggered Resolvin D1 (AT-RvD1) after disease onset reduces submandibular gland (SMG) inflammation in the SS-like NOD/ShiLtJ mice.
Methods: Female and male NOD/ShiLtJ mice were treated twice a wk for 8 wk starting at 12-wk and 16-wk of age, respectively, via tail vein injections with AT-RvD1 (0.1 mg/kg) or vehicle control (EtOH, 7.2%). At 20- and 24-wk of age, respectively, mice were euthanized in a CO₂ chamber and SMGs were removed for qPCR and Western blot analysis of SS-associated pro-inflammatory cytokines. Additionally, SMG tissue sections were processed for H&E staining and grading was performed to analyze lymphocytic infiltration.
Results: Pro-inflammatory cytokines were downregulated in SMG from female mice treated with AT-RvD1. In contrast, this downregulation was not observed in SMG from male or vehicle controls. Regarding lymphocytic infiltration, no significant changes were observed among the treated groups. Interestingly, a protein responsible for RvD1 synthesis, 5-lipoxygenase activating protein (5-LOXAP), was translocated into the nucleus of SMG cells from both AT-RvD1-treated female and male NOD/ShiLtJ mice, similar to what is observed in non-SS human minor salivary glands.
Conclusions: AT-RvD1 reverses pro-inflammatory cytokine upregulation in female NOD/ShiLtJ mouse SMG and aids 5-LOXAP translocation into the nucleus.