This study set out to examine if the administration of metabolite-derived dietary polyphenols suppressed DAMP signaling in enriched mice microglia. 

Chronic stress-induced inflammatory responses are mediated by danger-associated molecular pattern (DAMP) molecules, which act as upstream transcriptional activators of the NLRP3 inflammasome. Priming of the NLRP3 inflammasome increases both the release of inflammatory and neurotoxic cytokines, such as IL-1β, as well as susceptibility to psychiatric disorders. In previous studies conducted in our lab, polyphenolic compounds were found to ameliorate stress-induced depression in mouse models. However, the precise mechanism by which polyphenols act to mitigate depressive-like symptoms has not been identified. 

We found that dietary polyphenols ameliorated CUS-induced depression and anxiety phenotypes in mice induced by both initial and secondary stressors. We found that CUS caused robust upregulation of IL-1β mRNA in microglia, an effect that persisted for up to 4 weeks. Following the subthreshold US re-exposure, we observed upregulation of pro-IL-1β, which was subsequently prevented by treatment with dietary polyphenols. The receptor for advanced glycation end products (RAGE) messenger RNA was also upregulated, but toll-like receptor 4 (TLR-4) was not. Additionally, an increase in RAGE mRNA expression was observed when mice were exposed to US prior to the start of the CUS paradigm. Importantly, primary exposure to US was sufficient to increase RAGE mRNA expression. Treatment with polyphenols prevented upregulation of RAGE mRNA, which reflects the ability of polyphenols to reverse the nascent neuroinflammation that may have begun following primary exposure to US.