Department of Physiology, Second Military Medical University, Shanghai 200433, China.
School of Kinesiology, The Key Laboratory of Exercise and Health Sciences of Ministry of Education, Shanghai University of Sport, Shanghai 200438, China.
Brain Behav Immun. 2016 Aug;56:175-86. doi: 10.1016/j.bbi.2016.02.022. Epub 2016 Feb 27.
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.
雌激素水平下降与情绪障碍（如抑郁和焦虑）的增加有关。我们之前的研究表明，海马中炎症细胞因子水平的升高导致了啮齿动物雌激素缺乏引起的抑郁样行为。由于核苷酸结合寡聚化结构域样受体家族 pyrin 结构域包含 3（NLRP3）炎症小体在各种炎症性疾病中发挥关键作用，我们探讨了 NLRP3 炎症小体是否参与由雌激素缺乏引起的情感障碍。研究发现，卵巢切除增加了雌性小鼠海马体中 IL-1β 和 IL-18、NLRP3 表达和活性 caspase-1 的水平。卵巢切除还导致 TLR-2 和 TLR-4、活性 NF-κB、前 IL-1β 和前 IL-18 的水平增加。用炎症小体抑制剂 VX-765 治疗卵巢切除（OVX）小鼠可改善抑郁和焦虑样行为，并逆转海马体中 IL-1β 和 IL-18 水平的升高。17β-雌二醇（E2）和雌激素受体（ER）β激动剂而非 ERα 激动剂可逆转卵巢切除引起的抑郁和焦虑样行为以及增加的炎症指标。此外，卵巢切除导致 P2X7 受体（P2X7R）表达增加，E2 和 ERβ 激动剂也可逆转这一现象。我们的研究表明，雌激素缺乏导致 NLRP3 炎症小体激活，从而导致海马体的神经炎症和抑郁及焦虑。雌激素对海马体炎症和抑郁及焦虑样行为的调节依赖于 ERβ。NLRP3 炎症小体可能是雌激素缺乏相关情感障碍的潜在治疗靶点。
