Zhu Simeng, Chen Siyue, Ge Yingzhou, Zhou Fangyue, Su Kaizhen, Xu Congfeng, Wu Yanting, Huang Hefeng
Department of Cardiology, Sixth People's Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
Obstetrics and Gynecology Hospital, Institute of Reproduction and Development, Fudan University, Shanghai, China.
Commun Biol. 2025 Jun 6;8(1):879. doi: 10.1038/s42003-025-08298-z.
Hyperlipidemia contributes to low-grade inflammation and abnormal immune response, which is putatively involved in the development of pre-eclampsia (PE). As components of innate immune system, complements play a critical role in regulating inflammation. However, how cell-autonomous complement changes and works in PE remains elusive. In the current study, we established L-NAME-induced mice to manifest PE-like symptoms. In presence of high-fat diet (HFD) feeding, the PE-like symptoms were considerably aggravated, as well as down-regulated complement C3 in HFD/L-NAME mice trophoblasts. To explore the effect of C3 in PE development, we generated C3 overexpression and knockdown cell (Swan.71 and Swan.71) based on Swan.71, a trophoblast cell line. We found that Swan.71 cells display promoted proliferation, migration and invasion capability and less secretion of anti-angiogenetic cytokines, while Swan.71 showed highly-activated NLRP3 inflammasome and pyroptosis, which was also noted in HFD/L-NAME placentas, highlighting the contributing role of inflammation to PE. Indeed, pro-inflammatory cytokines were increased in placentas from HFD/L-NAME mice. The similar trends of C3 in trophoblast from severe PE patients supported the contribution role of C3 to PE pathogenesis. Thus, our study provides evidence that cell-autonomous complement C3 regulates NLRP3 inflammasome activation upon HFD exposure, affecting trophoblast cell function in PE development.
高脂血症会导致低度炎症和异常免疫反应，这可能与子痫前期（PE）的发生有关。作为先天免疫系统的组成部分，补体在调节炎症中起关键作用。然而，细胞自主补体在PE中如何变化和发挥作用仍不清楚。在本研究中，我们建立了L-NAME诱导的小鼠模型以表现出类似PE的症状。在高脂饮食（HFD）喂养的情况下，类似PE的症状明显加重，并且HFD/L-NAME小鼠滋养层细胞中的补体C3下调。为了探究C3在PE发生中的作用，我们基于滋养层细胞系Swan.71构建了C3过表达和敲低细胞（Swan.71和Swan.71）。我们发现Swan.71细胞表现出增殖、迁移和侵袭能力增强，抗血管生成细胞因子分泌减少，而Swan.71显示出高度激活的NLRP3炎性小体和细胞焦亡，这在HFD/L-NAME胎盘组织中也有发现，突出了炎症对PE的作用。事实上，HFD/L-NAME小鼠胎盘组织中的促炎细胞因子增加。重度PE患者滋养层细胞中C3的类似变化趋势支持了C3对PE发病机制的作用。因此，我们的研究提供了证据，表明细胞自主补体C3在HFD暴露时调节NLRP3炎性小体激活，影响PE发生过程中滋养层细胞的功能。
