Li Chunhui, Wu Huanghui, Sen Ta Na Ha, Wang Lu, Zhong Chuanqi, Deng Bin, Liu Cong, Bao Han, Sang Hanfei, Hou Lichao
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.
Translational Research Institute of Brain and Brain-Like Intelligence, Shanghai Fourth People's Hospital, School of Medicine, Tongji University, Shanghai 200434, PR China.
Brain Res. 2022 Dec 15;1797:148112. doi: 10.1016/j.brainres.2022.148112. Epub 2022 Oct 8.
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.
抑郁症伴有过度的神经炎症。肝脏X受体β（LXRβ）已被报道为一种新出现的可调节全身和器官炎症的靶点。然而，其减轻神经炎症的调节机制远未明确。在本研究中，通过慢性不可预测轻度应激（CUMS）和皮质酮（CORT）饮水诱导小鼠出现与抑郁症相关的行为。小鼠分别接受TO901317、PLX - 5622以及双侧基底外侧杏仁核（BLA）注射rAAV9 - hSyn - hM3D(Gq) - eGFP，以分别激活LXRβ、清除小胶质细胞和对BLA中的神经元进行药物遗传学激活，随后进行行为测试。研究了BLA中小胶质细胞的促炎和促吞噬激活，以及核因子κB（NF - κB）信号通路、NLRP3炎性小体激活和白细胞介素 - 1β（IL - 1β）释放。此外，检测了有或没有TO901317时CORT诱导的BV2细胞的促炎激活。在有或没有TO901317的HT22 - 原代小胶质细胞共培养系统中测量了由IL - 1β释放所指示的神经炎症。我们的结果表明，慢性应激诱导了与抑郁症相关的行为，同时伴有小胶质细胞的促炎和促吞噬激活，以及BLA中的NF - κB信号通路和NLRP3炎性小体激活。相应地，LXRβ的药理学激活在体内和体外均抑制了小胶质细胞的促炎和促吞噬激活，以及NF - κB信号通路和NLRP3炎性小体激活，以及IL - 1β释放。最后，清除小胶质细胞和对BLA中的神经元进行药物遗传学激活均保护小鼠免受慢性应激诱导的与抑郁症相关的行为。总体而言，神经元 - 小胶质细胞LXRβ的药理学激活通过抑制NF - κB信号通路和NLRP3炎性小体激活来调节过度的神经炎症，从而减轻与抑郁症相关的行为。
