Centre of Molecular Inflammation Research, Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway.
Department of Gynecology and Obstetrics, St. Olavs Hospital, Trondheim, Norway.
Front Immunol. 2020 Oct 8;11:564712. doi: 10.3389/fimmu.2020.564712. eCollection 2020.
Preeclampsia is a hypertensive and inflammatory pregnancy disorder associated with cholesterol accumulation and inflammation at the maternal-fetal interface. Preeclampsia can be complicated with fetal growth restriction (FGR) and shares risk factors and pathophysiological mechanisms with cardiovascular disease. Cholesterol crystal mediated NLRP3 inflammasome activation is central to cardiovascular disease and the pathway has been implicated in placental inflammation in preeclampsia. Direct maternal-fetal interaction occurs both in the uterine wall decidua and at the placental surface and these aligned sites constitute the maternal-fetal interface. This study aimed to investigate cholesterol crystal accumulation and NLRP3 inflammasome expression by maternal and fetal cells in the uterine wall decidua of normal and preeclamptic pregnancies. Pregnant women with normal ( = 43) and preeclamptic pregnancies with ( = 28) and without ( = 19) FGR were included at delivery. Cholesterol crystals were imaged in decidual tissue by both second harmonic generation microscopy and polarization filter reflected light microscopy. Quantitative expression analysis of NLRP3, IL-1β and cell markers was performed by immunohistochemistry and automated image processing. Functional NLRP3 activation was assessed in cultured decidual explants. Cholesterol crystals were identified in decidual tissue, both in the tissue stroma and near uterine vessels. The cholesterol crystals in decidua varied between pregnancies in distribution and cluster size. Decidual expression of the inflammasome components NLRP3 and IL-1β was located to fetal trophoblasts and maternal leukocytes and was strongest in areas of proximity between these cell types. Pathway functionality was confirmed by cholesterol crystal activation of IL-1β in cultured decidual explants. Preeclampsia without FGR was associated with increased trophoblast dependent NLRP3 and IL-1β expression, particularly in the decidual areas of trophoblast and leukocyte proximity. Our findings suggest that decidual accumulation of cholesterol crystals may activate the NLRP3 inflammasome and contribute to decidual inflammation and that this pathway is strengthened in areas with close maternal-fetal interaction in preeclampsia without FGR.
子痫前期是一种与胆固醇积累和母体-胎儿界面炎症相关的高血压和炎症性妊娠疾病。子痫前期可并发胎儿生长受限 (FGR)，并与心血管疾病具有共同的危险因素和病理生理机制。胆固醇晶体介导的 NLRP3 炎性小体激活是心血管疾病的核心，该途径已被牵连到子痫前期的胎盘炎症中。直接的母婴相互作用发生在子宫壁蜕膜和胎盘表面，这些对齐的部位构成了母体-胎儿界面。本研究旨在研究正常和子痫前期妊娠中母体和胎儿细胞在子宫壁蜕膜中的胆固醇晶体积累和 NLRP3 炎性小体表达。分娩时纳入正常妊娠妇女 (n=43)、子痫前期伴 FGR 妊娠妇女 (n=28) 和无 FGR 妊娠妇女 (n=19)。通过二次谐波产生显微镜和偏振滤光反射光显微镜对蜕膜组织中的胆固醇晶体进行成像。通过免疫组织化学和自动图像处理对 NLRP3、IL-1β 和细胞标志物进行定量表达分析。在培养的蜕膜外植体中评估功能性 NLRP3 激活。在蜕膜组织中鉴定到胆固醇晶体，分布在组织基质中和靠近子宫血管附近。蜕膜中的胆固醇晶体在妊娠之间的分布和簇大小上有所不同。炎性小体成分 NLRP3 和 IL-1β 在蜕膜中的表达定位于胎儿滋养层细胞和母体白细胞，在这些细胞类型之间接近的区域最强。通过胆固醇晶体在培养的蜕膜外植体中激活 IL-1β 证实了途径的功能。无 FGR 的子痫前期与依赖滋养层的 NLRP3 和 IL-1β 表达增加有关，特别是在滋养层和白细胞接近的蜕膜区域。我们的研究结果表明，胆固醇晶体在蜕膜中的积累可能激活 NLRP3 炎性小体并促进蜕膜炎症，并且在无 FGR 的子痫前期中，在接近母婴的区域，该途径得到加强。
