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

Xiujing Feng,Yujie Yao,Manyu Song,Honggang Fan,Yuan Zhao,Tianyuan Yang,Chaoran Wang

doi:10.3389/fnmol.2019.00210

Xiujing Feng, Yujie Yao + Show 5 more

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https://doi.org/10.3389/fnmol.2019.00210

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Abstract

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.

Highlights

Depression is a common mental disease with high morbidity, recurrence and mortality and is a serious global health problem (Yang et al, 2019)
Rats were randomly divided into two weight-matched groups: control group (C, n = 30) and chronic stress group (CS, n = 30). 12 rats in each group were used for behavioral experiments, and the remaining 18 were used for subsequent experiments
We speculated that chronic restraint stress would induce corticosterone release, which can be used as an index of HPA activation

Summary

Introduction

Depression is a common mental disease with high morbidity, recurrence and mortality and is a serious global health problem (Yang et al, 2019). Especially chronic stress, is considered an important risk factor for depression, and it severely impairs cognition and learning and memory functions (Hayden et al, 2010). GCs Triggers NLRP3 Inflammasome Activation axis, which results in persistent release of glucocorticoids throughout the brain (Rivier and Vale, 1983), especially the hippocampus (Zhao et al, 2015). Several studies have shown that the hippocampus, amygdala and the prefrontal cortex play major roles in depression (Price and Drevets, 2010). The hippocampus, a stress-sensitive limbic structure, is important for cognition and spatial memory, and these functions are impaired in depressive disorder (Austin et al, 2001). The hippocampus is intimately involved in the pathophysiology of depression

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