title: NLRP3 inflammasome activation mediates estrogen deficiency-induced depression- and anxiety-like behavior and hippocampal inflammation in mice.
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.
authors.affiliation: Department of Physiology, Second Military Medical University, Shanghai 200433, China.
authors.forename: Yongjun
authors.initials: Y
authors.lastname: Xu
authors.affiliation: Department of Physiology, Second Military Medical University, Shanghai 200433, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Sheng
authors.affiliation: Department of Physiology, Second Military Medical University, Shanghai 200433, China.
authors.forename: Qingyue
authors.initials: Q
authors.lastname: Bao
authors.affiliation: School of Kinesiology, The Key Laboratory of Exercise and Health Sciences of Ministry of Education, Shanghai University of Sport, Shanghai 200438, China.
authors.forename: Yujun
authors.initials: Y
authors.lastname: Wang
authors.affiliation: School of Kinesiology, The Key Laboratory of Exercise and Health Sciences of Ministry of Education, Shanghai University of Sport, Shanghai 200438, China.
authors.forename: Jianqiang
authors.initials: J
authors.lastname: Lu
authors.affiliation: Department of Physiology, Second Military Medical University, Shanghai 200433, China. Electronic address: nixin@smmu.edu.cn.
authors.forename: Xin
authors.initials: X
authors.lastname: Ni
mesh_terms: D000818:Animals; D001007:Anxiety / Q000378:metabolism*; D001522:Behavior, Animal / Q000502:physiology*; D003863:Depression / Q000378:metabolism*; D004967:Estrogens / Q000172:deficiency*; D005260:Female; D006624:Hippocampus / Q000276:immunology / Q000378:metabolism*; D058847:Inflammasomes / Q000378:metabolism*; D007249:Inflammation / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein / Q000378:metabolism*; D010052:Ovariectomy
chemical_list: D004967:Estrogens; D058847:Inflammasomes; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse
keywords: Anxiety; Depression; Estrogen; Hippocampus; Inflammation; NLRP3 inflammasome