Glucocorticoid-Driven NLRP3 Inflammasome Activation in Hippocampal Microglia Mediates Chronic Stress-Induced Depressive-Like Behaviors

• Published in: Frontiers in molecular neuroscience Vol. 12; p. 210
• Main Authors: Feng, Xiujing, Zhao, Yuan, Yang, Tianyuan, Song, Manyu, Wang, Chaoran, Yao, Yujie, Fan, Honggang
• Format: Journal Article
• Language: English
• Published: Lausanne Frontiers Research Foundation 29.08.2019; Frontiers Media S.A
• Subjects: Animal cognition; Antidepressants; Anxiety; Behavior; Caspase; Caspase-1; Cell culture; Corticosterone; Cytokines; depressive-like behaviors; Dexamethasone; Experiments; glucocorticoid; Glucocorticoids; hippocampal microglia; Hippocampus; IL-1β; Inflammasomes; Inflammation; Interleukin 18; Laboratory animals; Medical research; Mental depression; Microglia; Microglial cells; neuroinflammation; Neuroscience; Neurosciences; NF-κB protein; NLRP3 inflammasome; Pathogenesis; Proteins; Reactive oxygen species; Risk factors; Rodents; Stress; Studies; China
• ISSN: 1662-5099; 1662-5099
• DOI: 10.3389/fnmol.2019.00210

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 × 10-7 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 in vitro 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.