Aspirin Triggered Resolvin D1 reduces inflammation and restores saliva secretion in a Sjögren’s syndrome mouse model

Abstract

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.

Sex‐mediated elevation of the specialized pro‐resolving lipid mediator levels in a Sjögren's syndrome mouse model

“…As indicated above, our previous studies demonstrated that intravenous treatment with AT‐RvD1 in female NOD/ShiLtJ mice either before or after disease onset reverses SS‐like features 39,41 . Interestingly, in the current study we observed that levels of RvD1 are elevated in both plasma and saliva collected from post‐disease female mice as compared to their pre‐disease counterparts.…”

“…Our previous work demonstrated that systemic treatment with AT‐RvD1 prevents disease onset in the NOD/ShiLtJ mice 39 . Moreover, a similar treatment delivered after disease onset, diminished SS‐like features 41 . Together, these studies indicate a functional role for SPM biosynthesis in SS pathogenesis.…”

“…Previous studies showed that AT‐RvD1 treatment improved saliva secretion and reduced salivary gland inflammation in female mice after disease onset 41 . This raised the question whether alterations in SPM receptor expression cause a need for additional amounts of RvD1 for receptor activation.…”

“…A limitation of this experiment is the likelihood of a different situation when the treatment occurs during in vivo conditions. Particularly, previous studies demonstrated that intravenous AT‐RvD1 treatment of NOD/ShiLtJ at disease onset decreases SMG inflammation while restoring saliva secretion 39,41 …”

“…Studies using the non‐obese diabetic (NOD)/ShiLtJ SS mouse model indicate that treatment with AT‐RvD1 before disease onset maintains the integrity and function of the salivary gland epithelium thereby preventing the progression of the disease in vivo 39,40 . Treatment with AT‐RvD1 after disease onset restores salivary gland function and causes a reduction of Th17 cell infiltration in both female and male mice 41 . Mice lacking the RvD1 receptor ALX/FPR2 display impaired innate and adaptive immune responses in salivary glands (exacerbated inflammatory reaction and increased apoptosis) in response to systemic LPS treatment 42 .…”