Department of Obstetrics and Gynecology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Oxid Med Cell Longev. 2021 Nov 11;2021:1806344. doi: 10.1155/2021/1806344. eCollection 2021.
NOD-like receptor family, pyrin domain-containing protein 3 (NLRP3) inflammasome-mediated pyroptosis is a crucial event in the preeclamptic pathogenesis, tightly linked with the uteroplacental TLR4/NF-B signaling. Trophoblastic glycometabolism reprogramming has now been noticed in the preeclampsia pathogenesis, plausibly modulated by the TLR4/NF-B signaling as well. Intriguingly, cellular pyroptosis and metabolic phenotypes may be inextricably linked and interacted. Metformin (MET), a widely accepted NF-B signaling inhibitor, may have therapeutic potential in preeclampsia while the underlying mechanisms remain unclear. Herein, we investigated the role of MET on trophoblastic pyroptosis and its relevant metabolism reprogramming. The safety of pharmacologic MET concentration to trophoblasts was verified at first, which had no adverse effects on trophoblastic viability. Pharmacological MET concentration suppressed NLRP3 inflammasome-induced pyroptosis partly through inhibiting the TLR4/NF-B signaling in preeclamptic trophoblast models induced via low-dose lipopolysaccharide. Besides, MET corrected the glycometabolic reprogramming and oxidative stress partly via suppressing the TLR4/NF-B signaling and blocking transcription factor NF-B1 binding on the promoter PFKFB3, a potent glycolytic accelerator. Furthermore, PFKFB3 can also enhance the NF-B signaling, reduce NLRP3 ubiquitination, and aggravate pyroptosis. However, MET suppressed pyroptosis partly via inhibiting PFKFB3 as well. These results provided that the TLR4/NF-B/PFKFB3 pathway may be a novel link between metabolism reprogramming and NLRP3 inflammasome-induced pyroptosis in trophoblasts. Further, MET alleviates the NLRP3 inflammasome-induced pyroptosis, which partly relies on the regulation of TLR4/NF-B/PFKFB3-dependent glycometabolism reprogramming and redox disorders. Hence, our results provide novel insights into the pathogenesis of preeclampsia and propose MET as a potential therapy.
NOD 样受体家族，富含吡喃结构域蛋白 3（NLRP3）炎性体介导热激细胞程序性细胞死亡（pyroptosis）是子痫前期发病机制中的关键事件，与子宫胎盘 TLR4/NF-B 信号紧密相关。糖代谢重编程已在子痫前期发病机制中被注意到，可能同样受到 TLR4/NF-B 信号的调节。有趣的是，细胞热激细胞程序性细胞死亡和代谢表型可能存在不可分割的联系和相互作用。二甲双胍（MET）是一种广泛接受的 NF-B 信号抑制剂，可能在子痫前期中具有治疗潜力，但其潜在机制尚不清楚。在此，我们研究了 MET 对滋养层细胞热激细胞程序性细胞死亡及其相关代谢重编程的作用。首先验证了药物 MET 浓度对滋养层细胞的安全性，其对滋养层细胞活力无不良影响。药物 MET 浓度通过抑制低剂量脂多糖诱导的子痫前期滋养层模型中的 TLR4/NF-B 信号部分抑制 NLRP3 炎性体诱导的热激细胞程序性细胞死亡。此外，MET 通过抑制 TLR4/NF-B 信号并阻断转录因子 NF-B1 在糖酵解加速剂 PFKFB3 启动子上的结合，部分纠正糖代谢重编程和氧化应激。此外，PFKFB3 还可以增强 NF-B 信号，减少 NLRP3 泛素化，并加重热激细胞程序性细胞死亡。然而，MET 也通过抑制 PFKFB3 部分抑制热激细胞程序性细胞死亡。这些结果表明，TLR4/NF-B/PFKFB3 途径可能是滋养层细胞代谢重编程和 NLRP3 炎性体诱导的热激细胞程序性细胞死亡之间的新联系。此外，MET 减轻 NLRP3 炎性体诱导的热激细胞程序性细胞死亡，部分依赖于 TLR4/NF-B/PFKFB3 依赖性糖代谢重编程和氧化还原紊乱的调节。因此，我们的研究结果为子痫前期的发病机制提供了新的见解，并提出 MET 可能是一种潜在的治疗方法。
