Wang Xi, Shields Corbin A, Thompson Deanna, McKay Jie, Wilson Rachel, Robbins Marcus K, Glenn Hannah, Fontenot Molly, Williams Jan M, Cornelius Denise C
Department of Pharmacology and Toxicology, University of Mississippi Medical Center, Jackson, Mississippi, USA.
Department of Emergency Medicine, University of Mississippi Medical Center, Jackson, Mississippi, USA.
Am J Reprod Immunol. 2024 Jul;92(1):e13895. doi: 10.1111/aji.13895.
Preeclampsia (PE) is a hypertensive pregnancy disorder that is a leading cause of maternal and fetal morbidity and mortality characterized by maternal vascular dysfunction, oxidative stress, chronic immune activation, and excessive inflammation. No cure exists beyond delivery of the fetal-placental unit and the mechanisms driving pathophysiology are not fully understood. However, aberrant immune responses have been extensively characterized in clinical studies and shown to mediate PE pathophysiology in animal studies. One pathway that may mediate aberrant immune responses in PE is deficiencies in the IL-33 signaling pathway. In this study, we aim to investigate the impact of IL-33 signaling inhibition on cNK, T17, and T populations, vascular function, and maternal blood pressure during pregnancy.
In this study, IL-33 signaling was inhibited using two different methods: intraperitoneal administration of recombinant ST2 (which acts as a decoy receptor for IL-33) and administration of a specific IL-33 neutralizing antibody. Maternal blood pressure, uterine artery resistance index, renal and placental oxidative stress, cNK, T17, and T populations, various cytokines, and pre-proendothelin-1 levels were measured.
IL-33 signaling inhibition increased maternal blood pressure, uterine artery resistance, placental and renal oxidative stress. IL-33 signaling inhibition also increased placental cNK and T17 and renal T17 cells while decreasing placental T populations. IL-33 neutralization increased circulating cNK and T17s and decreased circulating Ts in addition to increasing pre-proendothelin-1 levels.
Data presented in this study demonstrate a role for IL-33 signaling in controlling vascular function and maternal blood pressure during pregnancy possibly by mediating innate and adaptive immune inflammatory responses, identifying the IL-33 signaling pathway as a potential therapeutic target for managing preeclampsia.
子痫前期（PE）是一种妊娠期高血压疾病，是孕产妇和胎儿发病及死亡的主要原因，其特征为母体血管功能障碍、氧化应激、慢性免疫激活和过度炎症反应。除了娩出胎儿 - 胎盘单位外，尚无治愈方法，且驱动病理生理学的机制尚未完全明确。然而，异常免疫反应在临床研究中已得到广泛描述，并在动物研究中显示介导了PE的病理生理学过程。IL - 33信号通路缺陷可能是介导PE异常免疫反应的一条途径。在本研究中，我们旨在探讨抑制IL - 33信号对妊娠期间循环自然杀伤细胞（cNK）、辅助性T细胞17（T17）和T细胞群体、血管功能及母体血压的影响。
在本研究中，采用两种不同方法抑制IL - 33信号：腹腔注射重组ST2（其作为IL - 33的诱饵受体）和给予特异性IL - 33中和抗体。测量母体血压、子宫动脉阻力指数、肾脏和胎盘的氧化应激、cNK、T17和T细胞群体、各种细胞因子以及前内皮素 - 1水平。
抑制IL - 33信号会升高母体血压、子宫动脉阻力、胎盘和肾脏的氧化应激。抑制IL - 33信号还会增加胎盘cNK和T17以及肾脏T17细胞，同时减少胎盘T细胞群体。中和IL - 33除了增加前内皮素 - 1水平外，还会增加循环cNK和T17细胞，并减少循环T细胞。
本研究呈现的数据表明，IL - 33信号在妊娠期间控制血管功能和母体血压方面发挥作用，可能是通过介导先天性和适应性免疫炎症反应，从而将IL - 33信号通路确定为管理子痫前期的潜在治疗靶点。
