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

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

  • Brain Behav Immun. 2016 Aug;56:175-86. doi: 10.1016/j.bbi.2016.02.022.
Yongjun Xu 1 Hui Sheng 1 Qingyue Bao 1 Yujun Wang 2 Jianqiang Lu 2 Xin Ni 3
Affiliations

Affiliations

  • 1 Department of Physiology, Second Military Medical University, Shanghai 200433, China.
  • 2 School of Kinesiology, The Key Laboratory of Exercise and Health Sciences of Ministry of Education, Shanghai University of Sport, Shanghai 200438, China.
  • 3 Department of Physiology, Second Military Medical University, Shanghai 200433, China. Electronic address: [email protected].
Abstract

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-1β 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-κB, pro-IL-1β 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-1β and IL-18 in hippocampus. Ovariectomy-induced depression- and anxiety-like behavior and increased inflammatory indicators were reversed by administration of 17β-estradiol (E2) and Estrogen Receptor (ER)β agonist but not ERα Agonist. In addition, ovariectomy led to increased expression of P2X7 receptor (P2X7R), which was also reversed by E2 and ERβ 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 ERβ dependent. NLRP3 inflammasome could be the potential therapeutic target for estrogen deficiency-related affective disorders.

Keywords

Anxiety; Depression; Estrogen; Hippocampus; Inflammation; NLRP3 inflammasome.

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