The Ferroptosis-NLRP1 Inflammasome: The Vicious Cycle of an Adverse Pregnancy.
The Ferroptosis-NLRP1 Inflammasome: The Vicious Cycle of an Adverse Pregnancy.
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DOI：
10.3389/fcell.2021.707959
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发表时间：
2021
影响因子：
5.5
通讯作者：
Huimin D
中科院分区：
文献类型：
--
作者：
Meihe L;Shan G;Minchao K;Xiaoling W;Peng A;Xili W;Jin Z;Huimin D
胎盘功能障碍的标志之一是氧化应激的增加。这个过程，加上炎症小体的过度表达，造成了螺旋式下降，可能导致一系列严重的妊娠并发症。铁死亡是铁介导的细胞死亡的一种形式，涉及活性氧、脂质过氧化物的积累。本研究建立大鼠氧化应激流产模型，并利用过氧化氢（H2O2）建立胎盘氧化应激细胞模型。采用RNAi、蛋白质印迹和免疫荧光法评估胎盘滋养层细胞铁死亡特异性标志物的表达和炎性小体的表达。我们在氧化应激的大鼠模型和胎盘滋养层细胞模型中观察到过量的铁死亡和炎症小体激活。当NLRP1炎症小体被沉默时，GSH和谷胱甘肽过氧化物酶4（GPX4）的表达水平升高，而转铁蛋白受体1（TFR1）、酰基辅酶A合成酶长链家族成员4（ACSL4）、超氧化物歧化酶（SOD）和丙二醛（MDA）的表达水平降低。然而，当应用 NLRP1 激活剂时，我们观察到相反的现象。我们进一步探讨了铁死亡对炎症小体作用的机制。应用铁死亡抑制剂（ferrostatin-1）和铁死亡激活剂（erastin）后，NLRP1、NLRP3、IL-1β和caspase-1的表达水平与铁死亡呈正相关。胎盘滋养层细胞氧化应激模型证实铁死亡的存在；结果还表明铁死亡与 NLRP1 炎性体的表达有关。这些发现可能为妊娠相关疾病的发病机制提供有价值的治疗靶点。
One of the hallmarks of placental dysfunction is the increase of oxidative stress. This process, along with the overexpression of the inflammasome, creates a downward spiral that can lead to a series of severe pregnancy complications. Ferroptosis is a form of iron-mediated cell death involving the accumulation of reactive oxygen species, lipid peroxides. In this study, the rats’ model of oxidative stress abortion was established, and hydrogen peroxide (H2O2) was used to establish a cellular model of placental oxidative stress. RNAi, western blot, and immunofluorescence were used to evaluate the expression of specific markers of ferroptosis and the expression of the inflammasome in placental trophoblast cells. We observed excessive levels of ferroptosis and inflammasome activation in both rats’ model and placental trophoblast cell model of oxidative stress. When the NLRP1 inflammasome was silenced, the expression levels of GSH and Glutathione peroxidase 4 (GPX4) were increased, while the expression levels of transferrin receptor 1 (TFR1), acyl-CoA synthetase long-chain family member 4 (ACSL4), Superoxide dismutase (SOD), and Malondialdehyde (MDA) were decreased. However, when an NLRP1 activator was applied, we observed the opposite phenomenon. We further explored the mechanisms underlying the actions of ferroptosis to inflammasomes. The expression levels of NLRP1, NLRP3, IL-1β, and caspase-1 were positively correlated with the ferroptosis following the application of ferroptosis inhibitor (ferrostatin-1) and ferroptosis activator (erastin). The existence of ferroptosis was demonstrated in the oxidative stress model of placental trophoblast cells; the results also indicate ferroptosis is linked with the expression of NLRP1 inflammasome. These findings may provide a valuable therapeutic target for the pathogenesis of pregnancy-related diseases.
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影响因子：
1.5
作者：
Ahmadi, Reza;Rahimi, Zohreh;Rahimi, Ziba
通讯作者：
Rahimi, Ziba
ACSL4 通过塑造细胞脂质成分来决定铁死亡敏感性。
影响因子：
14.8
作者：
Doll S;Proneth B;Tyurina YY;Panzilius E;Kobayashi S;Ingold I;Irmler M;Beckers J;Aichler M;Walch A;Prokisch H;Trümbach D;Mao G;Qu F;Bayir H;Füllekrug J;Scheel CH;Wurst W;Schick JA;Kagan VE;Angeli JP;Conrad M
通讯作者：
Conrad M
影响因子：
64.5
作者：
Dixon SJ;Lemberg KM;Lamprecht MR;Skouta R;Zaitsev EM;Gleason CE;Patel DN;Bauer AJ;Cantley AM;Yang WS;Morrison B 3rd;Stockwell BR
通讯作者：
Stockwell BR
白藜芦醇对胎盘滋养层氧化应激模型自噬和炎症小体表达的影响
影响因子：
6.1
作者：
Li, Meihe;Wu, Xiaoling;Liu, Runxia
通讯作者：
Liu, Runxia
影响因子：
9.5
作者：
An, Peijing;Gao, Zhiguo;Sun, Baiwang
通讯作者：
Sun, Baiwang