Chen Yuanyao, Xiao Lin, Sun Guoqiang, Li Min, Yang Hailan, Ming Zhangyin, Zhao Kai, Shang Xuejun, Zhang Huiping, Liu Chunyan
Institute of Reproductive Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
Department of Obstetrics and Gynecology, Maternal and Child Hospital of Hubei Province, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
Biology (Basel). 2023 Jan 29;12(2):208. doi: 10.3390/biology12020208.
Impaired invasion of EVTs results in inadequate remodelling of arteries and poor placentation, leading to PE. TMBIM4 was found to promote the migration and invasion of human osteosarcoma U2-OS and breast cancer MCF7 cell lines. However, the effect of TMBIM4 on trophoblast biological behaviour and its relevance to PE pathophysiology remain unclear. In this study, we confirmed that TMBIM4 was highly expressed in cytotrophoblasts, syncytiotrophoblasts, and EVTs of the human placenta during early pregnancy. By comparing the expression levels of TMBIM4 in the placenta of women with normal-term pregnancy and PE, TMBIM4 was found to be significantly decreased in PE. Thereafter, we determined the expression of TMBIM4 in the LPS-treated first-trimester human trophoblast cell line HTR-8/SVneo (mimicking a PE-like cell model), and determined the effect of TMBIM4 on trophoblast function and its underlying mechanism. LPS treatment reduced the expression of TMBIM4 and induced NLRP3 inflammasome activity in HTR-8/SVneo cells. KO of TMBIM4 in the HTR-8/SVneo cell line impaired cell viability, migration, and invasion, which was more severe in the LPS/ATP-treated TMBIM4-KO cell line. Moreover, TMBIM4 deficiency enhanced NLRP3 inflammasome activity and promoted subsequent pyroptosis, with or without LPS/ATP treatment. The negative relationship between TMBIM4 expression and NLRP3 inflammatory activity was verified in PE placentas. Inhibiting the NLRP3 inflammasome with MCC950 in HTR-8/SVneo cells alleviated LPS/ATP-induced pyroptosis and damaged cell function in the TMBIM4-KO cell line. Overall, this study revealed a new PE-associated protein, TMBIM4, and its biological significance in trophoblast pyroptosis mediated by the NLRP3 inflammasome. TMBIM4 may serve as a potential target for the treatment of placental inflammation-associated PE.
绒毛外滋养层细胞（EVT）侵袭受损会导致动脉重塑不足和胎盘形成不良，进而引发子痫前期（PE）。研究发现跨膜Bax抑制因子4（TMBIM4）可促进人骨肉瘤U2-OS细胞系和乳腺癌MCF7细胞系的迁移和侵袭。然而，TMBIM4对滋养层细胞生物学行为的影响及其与PE病理生理学的相关性仍不明确。在本研究中，我们证实TMBIM4在妊娠早期人胎盘的细胞滋养层细胞、合体滋养层细胞和EVT中高表达。通过比较正常足月妊娠和PE孕妇胎盘组织中TMBIM4的表达水平，发现PE患者胎盘组织中TMBIM4显著降低。此后，我们检测了脂多糖（LPS）处理的孕早期人滋养层细胞系HTR-8/SVneo（模拟PE样细胞模型）中TMBIM4的表达，并确定了TMBIM4对滋养层细胞功能的影响及其潜在机制。LPS处理降低了HTR-8/SVneo细胞中TMBIM4的表达，并诱导了NLRP3炎性小体活性。在HTR-8/SVneo细胞系中敲除TMBIM4会损害细胞活力、迁移和侵袭能力，在LPS/ATP处理的TMBIM4敲除细胞系中这种损害更为严重。此外，无论是否进行LPS/ATP处理，TMBIM4缺乏均增强了NLRP3炎性小体活性并促进了随后的细胞焦亡。在PE胎盘组织中证实了TMBIM4表达与NLRP3炎症活性之间呈负相关。在HTR-8/SVneo细胞中用MCC950抑制NLRP3炎性小体可减轻LPS/ATP诱导的细胞焦亡，并改善TMBIM4敲除细胞系中受损的细胞功能。总体而言，本研究揭示了一种新的与PE相关的蛋白TMBIM4及其在NLRP3炎性小体介导的滋养层细胞焦亡中的生物学意义。TMBIM4可能作为治疗胎盘炎症相关PE的潜在靶点。
