Endoplasmic reticulum stress may activate NLRP3 inflammasomes via TXNIP in preeclampsia.
Endoplasmic reticulum stress may activate NLRP3 inflammasomes via TXNIP in preeclampsia.
复制标题
在先兆子痫中，内质网应激可能通过 TXNIP 激活 NLRP3 炎症小体。
DOI：
10.1007/s00441-019-03104-9
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发表时间：
2019
期刊：
影响因子：
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通讯作者：
Zhang H
中科院分区：
文献类型：
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作者：
Yang Y;Li J;Han TL;Zhou X;Qi H;Baker PN;Zhou W;Zhang H
子痫前期(PE)的发展通常与胎盘免疫和炎症调节失调以及内质网(ER)应激有关。然而，内质网应激和炎性调节失调与PE之间的联系机制尚未阐明。已有研究表明，硫氧还蛋白相互作用蛋白(TXNIP)是免疫调节中的一个关键点，它可以与NLR家族的含3(NLRP3)结构域的炎症体结合并激活。最近的实验证据表明，活化的NLRP3炎性小体可以激活PE患者胎盘中白细胞介素1β(IL-1β)的产生。本研究的目的是探讨TXNIP是否在内质网应激与NLRP3炎性小体激活之间起着关键的信号作用。我们推测内质网应激可诱导TXNIP的产生，TXNIP可与NLRP3炎性小体结合，激活IL-1β的产生。这些细胞表现出较高的NLRP3和IL-1β蛋白水平，以及较高的caspase-1酶活性，表明炎症调节失调和内质网应激加剧。转染TXNIP siRNA的细胞显示NLRP3炎性小体活性降低。用内质网应激抑制剂4-苯丁酸处理的细胞也显示出类似的结果。用TXNIP慢病毒外植体在H/R或衣霉素(ER胁迫诱导剂)中的生长也被测量以验证我们的假设。提示TXNIP可通过介导内质网应激和NLRP3炎性小体激活来影响炎症调节紊乱。这一新的机制可能进一步解释在母胎界面观察到的炎症，这导致PE患者的胎盘功能障碍。
Preeclampsia (PE) development is often associated with placental immune and inflammatory dysregulation, as well as endoplasmic reticulum (ER) stress. However, the mechanisms linking ER stress and inflammatory dysregulation to PE have not been elucidated. It has been reported that thioredoxin-interacting protein (TXNIP), which can bind with and activate the NLR family pyrin domain containing 3 (NLRP3) inflammasome, is a key point in immune regulation. Recent experimental evidence suggests that activated NLRP3 inflammasomes can activate interleukin-1β (IL-1β) production in the placenta of patients with PE. The objective of the current study was to explore if TXNIP plays a critical signaling role linking ER stress with NLRP3 inflammasome activation in PE. We hypothesized that ER stress would induce TXNIP production, which would bind with NLRP3 inflammasomes to activate IL-1β production. These cells showed a higher protein level of NLRP3 and IL-1β, as well as a higher enzymatic activity of caspase-1, indicating enhanced inflammatory dysregulation and ER stress. Cells transfected with TXNIP siRNA showed reduced NLRP3 inflammasome activation. Cells treated with 4-phenylbutyric acid, an inhibitor of ER stress, showed a similar result. Outgrowth of the explant with TXNIP lentivirus in H/R or tunicamycin (inducers of ER stress) was also measured to verify our hypothesis. These findings demonstrated that TXNIP could influence inflammatory dysregulation by mediating ER stress and NLRP3 inflammasome activation in PE. This novel mechanism may further explain the inflammation observed at the maternal-fetal interface, which leads to placental dysfunction in a patient with PE.