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

Chunhui Li; Huanghui Wu; Ha Sen Ta Na; Lu Wang; Chuanqi Zhong; Bin Deng; Cong Liu; Han Bao; Hanfei Sang; Lichao Hou

doi:10.1016/j.brainres.2022.148112

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

Brain Res. 2022 Dec 15:1797:148112. doi: 10.1016/j.brainres.2022.148112. Epub 2022 Oct 8.

Authors

Chunhui Li¹, Huanghui Wu², Ha Sen Ta Na³, Lu Wang⁴, Chuanqi Zhong⁵, Bin Deng⁴, Cong Liu⁴, Han Bao⁴, Hanfei Sang⁴, Lichao Hou⁶

Affiliations

¹ Department of Anesthesiology, Xiang'an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen 361102, PR China; Department of Anesthesiology, the Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School, Nanjing Medical University, Suzhou 215000, PR China.
² Translational Research Institute of Brain and Brain-Like Intelligence, Shanghai Fourth People's Hospital, School of Medicine, Tongji University, Shanghai 200434, PR China.
³ Department of Anesthesiology, Inner Mongolia Autonomous Region People's Hospital, Hohhot 010017, PR China.
⁴ Department of Anesthesiology, Xiang'an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen 361102, PR China.
⁵ School of Life Science, Xiamen University, Xiamen 361102, PR China.
⁶ Department of Anesthesiology, Xiang'an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen 361102, PR China. Electronic address: lchou@xah.xmu.edu.cn.

PMID: 36216100
DOI: 10.1016/j.brainres.2022.148112

Abstract

Depression is accompanied by excessive neuroinflammation. Liver X receptor β (LXRβ) 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 LXRβ, 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-κB (NF-κB) signaling pathway, NLRP3 inflammasome activation and interleukin-1β (IL-1β) 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-1β 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-κB signaling pathway and NLRP3 inflammasome activation in BLA. Accordingly, pharmacological activation of LXRβ inhibited microglial pro-inflammatory and pro-phagocytic activation, as well as NF-κB signaling pathway and NLRP3 inflammasome activation, and IL-1β 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 activation of neuronal-microglial LXRβ alleviates depression-related behavior by modulating excessive neuroinflammation via inhibiting NF-κB signaling pathway and NLRP3 inflammasome activation.

Keywords: Basolateral amygdala; Chronic unpredictable mild stress; Depression-related behavior; Liver X receptor β; Microglia; Neuroinflammation.