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Objectives: SS is characterized by chronic inflammation of the salivary glands leading to loss of secretory function, thereby suggesting specialized pro-resolving mediators targeting inflammation to be a viable option for treating SS. Previous studies demonstrated that aspirin-triggered resolvin D1 (AT-RvD1) prevents chronic inflammation and enhances saliva secretion in a SS-like mouse model when applied before disease onset. However, this therapy cannot be used in SS patients given that diagnosis occurs post-disease onset and no reliable screening methods exist. Therefore, we examined whether treatment with AT-RvD1 reduces SS-like features in a mouse model post-disease onset., Methods: Tail vein injections were performed in a SS-like mouse model both with and without AT-RvD1 post-disease onset for 8 weeks, with salivary gland function and inflammatory status subsequently determined., Results: Treatment of a SS-like mouse model with AT-RvD1 post-disease onset restores saliva secretion in both females and males. Moreover, although AT-RvD1 treatment does not reduce the overall submandibular gland lymphocytic infiltration, it does reduce the number of T helper 17 cells within the infiltrates in both sexes. Finally, AT-RvD1 reduces SS-associated pro-inflammatory cytokine gene and protein expression levels in submandibular glands from female but not male mice., Conclusion: AT-RvD1 treatment administered post-disease onset reduces T helper 17 cells and successfully restores salivary gland function in a SS mouse model with variable effects noted by sex, thus warranting further examination of both the causes for the sex differences and the mechanisms responsible for the observed treatment effect., (© The Author(s) 2019. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Sjögren's syndrome (SS) is a chronic inflammatory autoimmune disease characterized by diminished secretory function of the exocrine glands. Treatments for hyposalivation are limited to the use of saliva substitutes and medications that provide only temporary relief. In light of the high degree of need and the limitations of current therapies, development of alternative treatments to restore functioning is essential. Resolvins (Rv), which are highly potent lipid mediators, offer a viable alternative for better treating inflammatory diseases such as SS. The goal of this study was to determine whether systemic preventive treatment with Aspirin-triggered RvD1 (AT-RvD1) reduces inflammation and preserves secretory functioning in NOD/ShiLtJ SS-like mice. Our results indicate that systemic treatment with AT-RvD1 diminishes the progression of the disease in salivary epithelium from female mice as follows: (a) improves secretory function, (b) reduces pro-inflammatory molecule gene expression, (c) increases anti-inflammatory molecule gene expression and (d) induces M2 macrophage polarization. Finally, AT-RvD1 decreases lymphocytic infiltration into the salivary glands when used with small doses of the steroid, dexamethasone, and promotes the tissue healing process.

Sjögren's syndrome (SS) is an autoimmune disorder characterized by chronic inflammation and destruction of salivary and lacrimal glands leading to dry mouth and dry eyes, respectively. Currently, the etiology of SS is unknown and the current therapies have no permanent benefit; therefore, new approaches are necessary to effectively treat this condition. Resolvins are highly potent endogenous lipid mediators that are synthesized during the resolution of inflammation to restore tissue homeostasis. Previous studies indicate that the resolvin family member, RvD1, binds to the ALX/FPR2 receptor to block inflammatory signals caused by tumor necrosis factor-alpha (TNF-α) in the salivary epithelium. More recently, the corticosteroid, dexamethasone (DEX), was shown to be effective in reducing salivary gland inflammation. However, DEX, as with other corticosteroids, elicits adverse secondary effects that could be ameliorated when used in smaller doses. Therefore, we investigated whether the more stable aspirin-triggered (AT) epimer, AT-RvD1, combined with reduced doses of DEX is effective in treating TNF-α-mediated disruption of polarized rat parotid gland (Par-C10) epithelial cell clusters. Our results indicate that AT-RvD1 and DEX individually reduced TNF-α-mediated alteration in the salivary epithelium (i.e, maintained cell cluster formation, increased lumen size, reduced apoptosis, and preserved cell survival signaling responses) as compared to untreated cells. Furthermore, AT-RvD1 combined with a reduced dose of DEX produced stronger responses (i.e., robust salivary cell cluster formation, larger lumen sizes, further reduced apoptosis, and sustained survival signaling responses) as compared to those observed with individual treatments. These studies demonstrate that AT-RvD1 combined with DEX is highly effective in treating TNF-α-mediated disruption of salivary gland epithelium., (© 2016 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of the American Physiological Society and The Physiological Society.)