NLRP3 inflammasome activation mediates estrogen deficiency-induced depression- and anxiety-like behavior and hippocampal inflammation in mice

Decline of estrogen level is associated with an increase in mood disturbances such as depression and anxiety. Our previous study showed that increased levels of inflammatory cytokines in hippocampus contribute to estrogen deficiency-induced depression-like behavior in rodents. Since the nucleotide binding and oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome plays a critical role in various inflammatory diseases, we explored whether NLRP3 inflammasome is involved in affective disorders caused by estrogen deficiency. It was found that ovariectomy increased the levels of IL-1 beta and IL-18, NLRP3 expression and active caspase-1 in hippocampus of female mice. Ovariectomy also resulted in an increase in the level of TLR-2 and TLR-4, active NF-kappa B, pro-IL-1 beta and pro-IL-18. Treatment of ovariectomized (OVX) mice with inflammasome inhibitor VX-765 ameliorated depression- and anxiety-like behavior and reversed increased levels of IL-1 beta and IL-18 in hippocampus. Ovariectomy-induced depression- and anxiety-like behavior and increased inflammatory indicators were reversed by administration of 17 beta-estradiol (E-2) and estrogen receptor (ER)8 agonist but not ER alpha. agonist. In addition, ovariectomy led to increased expression of P2X7 receptor (P2X7R), which was also reversed by E-2 and ER beta agonist. Our study suggests that estrogen deficiency results in NLRP3 inflammasome activation, thereby leading to neuroinflammation in hippocampus and depression and anxiety. Estrogen modulation of inflammation in hippocampus and depression- and anxiety-like behavior is ER beta dependent. NLRP3 inflammasome could be the potential therapeutic target for estrogen deficiency-related affective disorders. (C) 2016 Elsevier Inc. All rights reserved.