Augmented trophoblast cell death in preeclampsia can proceed via ceramide-mediated necroptosis.
Augmented trophoblast cell death in preeclampsia can proceed via ceramide-mediated necroptosis.
复制标题
子痫前期滋养细胞增强死亡可通过神经酰胺介导的坏死坏死进行。
DOI：
10.1038/cddis.2016.483
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发表时间：
2017-02-02
影响因子：
9
通讯作者：
Caniggia I
中科院分区：
文献类型：
--
作者：
Bailey LJ;Alahari S;Tagliaferro A;Post M;Caniggia I
子痫前期是一种严重的妊娠期高血压疾病，其特征是神经酰胺(CER)含量升高，这是通过细胞凋亡和自噬导致滋养层细胞死亡率增加的原因。滋养层细胞是否发生坏死性下垂，这是一种新的调节性坏死的特征形式，以及CER在这一过程中的潜在作用仍有待确定。在此，我们报道了JEG3细胞和原代分离的细胞滋养层细胞在C16：0CER和caspase-8抑制剂(Q-VD-Oph)的共同作用下促进了坏死性细胞的死亡，这是通过增加受体相互作用的蛋白激酶RIP1和RIP3的表达和关联，以及混合谱系激酶结构域样蛋白(MLKL)的磷酸化来证明的。坏死下垂抑制剂NEC-1(NEC-1)可抑制MLKL的活化和寡聚。CER+Q-VD-OPH处理的原代滋养层细胞表现出显著的坏死形态和破坏的融合过程，E-钙粘素染色的膜边界保持不变，胶质细胞缺失-1表达减少，但NEC-1有效地逆转了这些事件。与临床相关的是，我们发现与正常血压对照组相比，子痫前期患者胎盘对坏死性细胞死亡的易感性增加。在子痫前期，坏死体(RIP1/RIP3)蛋白水平升高，MLKL激活和寡聚化与坏死的细胞滋养层形态相关。此外，在重度早发性子痫前期患者中，caspase-8活性降低。这项研究首次报道了滋养层细胞经历CER诱导的坏死性细胞死亡，从而导致先兆子痫患者胎盘功能障碍和细胞死亡增加。
Preeclampsia, a serious hypertensive disorder of pregnancy, is characterized by elevated ceramide (CER) content that is responsible for heightened trophoblast cell death rates via apoptosis and autophagy. Whether trophoblast cells undergo necroptosis, a newly characterized form of regulated necrosis, and the potential role of CER in this process remain to be established. Herein, we report that exposure of both JEG3 cells and primary isolated cytotrophoblasts to C16:0 CER in conjunction with a caspase-8 inhibitor (Q-VD-OPh) promoted necroptotic cell death, as evidenced by increased expression and association of receptor-interacting protein kinases RIP1 and RIP3, as well as phosphorylation of mixed lineage kinase domain-like (MLKL) protein. MLKL activation and oligomerization could be abrogated by pretreatment with the necroptosis inhibitor necrostatin-1 (Nec-1). CER+Q-VD-OPH-treated primary trophoblasts displayed striking necrotic morphology along with disrupted fusion processes as evidenced by maintenance of E-cadherin-stained membrane boundaries and reduced glial cell missing-1 expression, but these events were effectively reversed using Nec-1. Of clinical relevance, we established an increased susceptibility to necroptotic cell death in preeclamptic placentae relative to normotensive controls. In preeclampsia, increased necrosome (RIP1/RIP3) protein levels, as well as MLKL activation and oligomerization associated with necrotic cytotrophoblast morphology. In addition, caspase-8 activity was reduced in severe early-onset preeclampsia cases. This study is the first to report that trophoblast cells undergo CER-induced necroptotic cell death, thereby contributing to the increased placental dysfunction and cell death found in preeclampsia.