Neuronal-microglial liver X receptor ? activating decrease neuroinflammation and chronic stress-induced depression-related behavior in mice

Depression is accompanied by excessive neuroinflammation. Liver X receptor beta (LXR beta) has been reported as a newly emerging target that exerts systemic and organic inflammation modulation. However, the modulatory mechanism in alleviating neuroinflammation are far from being revealed. In the current study, depression-related behaviors in mice were induced by chronic unpredictable mild stress (CUMS) and corticosterone (CORT) drinking. Mice received either TO901317, PLX-5622 and intra-bilateral basolateral amygdale (BLA) injection of rAAV9-hSyn-hM3D(Gq)-eGFP to activate LXR beta, eliminate microglia and pharmacogenetic activate neurons in BLA, respectively, followed by behavioral tests. Microglial pro-inflammatory and pro-phagocytic activation, as well as nuclear factor-kappa B (NF-kappa B) signaling pathway, NLRP3 inflammasome activation and inter-leukin-1 beta (IL-1 beta) release in BLA were investigated. Moreover, pro-inflammatory activation of BV2 cells-induced by CORT with or without TO901317 was detected. Neuroinflammation indicated by IL-1 beta release was measured in a co-culture system of HT22-primary microglia with or without TO901317. Our results indicated that chronic stress induced depression-related behaviors, which were accompanied with microglial pro-inflammatory and pro-phagocytic activation, as well as NF-kappa B signaling pathway and NLRP3 inflammasome activation in BLA. Accordingly, pharmacological activation of LXR beta inhibited microglial pro-inflammatory and pro-phagocytic activation, as well as NF-kappa B signaling pathway and NLRP3 inflammasome activation, and IL-1 beta release both in vivo and in vitro. Finally, both elimination of microglia and pharmacogenetic activation of neurons in BLA protected mice from chronic stress-induced depression-related behavior. Collectively, pharmacological activa-tion of neuronal-microglial LXR beta alleviates depression-related behavior by modulating excessive neuro -inflammation via inhibiting NF-kappa B signaling pathway and NLRP3 inflammasome activation.

Automated summary

This study found that chronic stress induces depression-related behaviors accompanied by microglial activation. By activating LXRβ and inhibiting the NF-κB signaling pathway and NLRP3 inflammasome activation, excessive neuroinflammation and depression-related behaviors can be alleviated.