Feng Xiujing, Zhao Yuan, Yang Tianyuan, Song Manyu, Wang Chaoran, Yao Yujie, Fan Honggang
Heilongjiang Key Laboratory for Laboratory Animals and Comparative Medicine, College of Veterinary Medicine, Northeast Agricultural University, Harbin, China.
Front Mol Neurosci. 2019 Aug 29;12:210. doi: 10.3389/fnmol.2019.00210. eCollection 2019.
Chronic stress is a key risk factor for depression, and microglia have been implicated in the pathogenesis of the disease. Recent studies show that the Nod-like receptor protein 3 (NLRP3) inflammasome is expressed in microglia and may play a crucial role in depression. However, the mechanism of NLRP3 inflammasome activation in hippocampal microglia and its role in depressive-like behaviors remain poorly understood. In this study, rats were subjected to 6 h of restraint stress per day for 21 days to produce a model of stress-induced depression. Behavioral tests and serum corticosterone were used to assess the success of the model. Furthermore, HAPI cells were pretreated with dexamethasone (5 × 10 M) to assess stress-induced changes in microglial cells in culture. The microglial marker Iba-1, reactive oxygen species (ROS), nuclear factor kappa B (NF-κB) and key components of the NLRP3 inflammasome and its downstream inflammatory effectors (IL-1β and IL-18) were measured. Chronic stress induced depressive-like behavior, increased serum corticosterone levels and produced hippocampal structural changes. Chronic stress and dexamethasone both increased Iba-1 expression and ROS formation and also elevated levels of NF-κB, NLRP3, cleaved caspase-1, IL-1β and IL-18. After use of the NF-κB inhibitor BAY 117082 and knocked out NLRP3 decreased ROS formation and the expression of Iba-1, NF-κB and NLRP3 as well as levels of cleaved caspase-1, IL-1β and IL-18. These findings suggest that activation of the glucocorticoid receptor-NF-κB-NLRP3 pathway in hippocampal microglia mediates chronic stress-induced hippocampal neuroinflammation and depression-like behavior.
慢性应激是抑郁症的关键风险因素，小胶质细胞与该疾病的发病机制有关。最近的研究表明，NOD样受体蛋白3（NLRP3）炎性小体在小胶质细胞中表达，可能在抑郁症中起关键作用。然而，海马小胶质细胞中NLRP3炎性小体激活的机制及其在抑郁样行为中的作用仍知之甚少。在本研究中，大鼠每天接受6小时的束缚应激，持续21天，以建立应激诱导的抑郁症模型。行为测试和血清皮质酮用于评估模型的成功与否。此外，用 dexamethasone（5×10⁻⁶ M）预处理HAPI细胞，以评估培养中小胶质细胞的应激诱导变化。检测小胶质细胞标志物Iba-1、活性氧（ROS）、核因子κB（NF-κB）以及NLRP3炎性小体的关键成分及其下游炎症效应因子（IL-1β和IL-18）。慢性应激诱导抑郁样行为，增加血清皮质酮水平并导致海马结构改变。慢性应激和dexamethasone均增加Iba-1表达和ROS形成，同时也提高NF-κB、NLRP3、裂解的caspase-1、IL-1β和IL-18的水平。使用NF-κB抑制剂BAY 11-7082并敲除NLRP3后，ROS形成以及Iba-1、NF-κB和NLRP3的表达以及裂解的caspase-1、IL-1β和IL-18的水平均降低。这些发现表明，海马小胶质细胞中糖皮质激素受体-NF-κB-NLRP3途径的激活介导了慢性应激诱导的海马神经炎症和抑郁样行为。
