BACKGROUND:Preeclampsia is a serious disease of pregnancy that lacks early diagnosis methods or effective treatment, except delivery. Dysregulated uterine immune cells and spiral arteries are implicated in preeclampsia, but the mechanistic link remains unclear.METHODS:Single-cell RNA sequencing and spatial transcriptomics were used to identify immune cell subsets associated with preeclampsia. Cell-based studies and animal models including conditional knockout mice and a new preeclampsia mouse model induced by recombinant mouse galectin-9 were applied to validate the pathogenic role of a CD11c^high subpopulation of decidual macrophages (dMφ) and to determine its underlying regulatory mechanisms in preeclampsia. A retrospective preeclampsia cohort study was performed to determine the value of circulating galectin-9 in predicting preeclampsia.RESULTS:We discovered a distinct CD11c^high dMφ subset that inhibits spiral artery remodeling in preeclampsia. The proinflammatory CD11c^high dMφ exhibits perivascular enrichment in the decidua from patients with preeclampsia. We also showed that trophoblast-derived galectin-9 activates CD11c^high dMφ by means of CD44 binding to suppress spiral artery remodeling. In 3 independent preeclampsia mouse models, placental and plasma galectin-9 levels were elevated. Galectin-9 administration in mice induces preeclampsia-like phenotypes with increased CD11c^high dMφ and defective spiral arteries, whereas galectin-9 blockade or macrophage-specific CD44 deletion prevents such phenotypes. In pregnant women, increased circulating galectin-9 levels in the first trimester and at 16 to 20 gestational weeks can predict subsequent preeclampsia onset.CONCLUSIONS:These findings highlight a key role of a distinct perivascular inflammatory CD11c^high dMφ subpopulation in the pathogenesis of preeclampsia. CD11c^high dMφ activated by increased galectin-9 from trophoblasts suppresses uterine spiral artery remodeling, contributing to preeclampsia. Increased circulating galectin-9 may be a biomarker for preeclampsia prediction and intervention.

中文翻译：

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半乳糖凝集素 9 驱动的 CD11chigh 蜕膜巨噬细胞亚群抑制先兆子痫的子宫血管重塑

背景：子痫前期是一种严重的妊娠期疾病，除分娩外缺乏早期诊断方法或有效治疗。子宫免疫细胞和螺旋动脉失调与先兆子痫有关，但其机制联系仍不清楚。方法：采用单细胞RNA测序和空间转录组学来鉴定与先兆子痫相关的免疫细胞亚群。基于细胞的研究和动物模型（包括条件敲除小鼠和重组小鼠半乳糖凝集素 9 诱导的新先兆子痫小鼠模型）用于验证蜕膜巨噬细胞 CD11c^高亚群 (dMφ) 的致病作用，并确定其在先兆子痫。进行了一项回顾性先兆子痫队列研究，以确定循环半乳糖凝集素 9 在预测先兆子痫中的价值。结果：我们发现了一个独特的 CD11c^高dMφ 子集，可抑制先兆子痫的螺旋动脉重塑。促炎性 CD11c^高dMφ 在先兆子痫患者的蜕膜中表现出血管周围富集。我们还表明，滋养层来源的半乳糖凝集素 9通过与 CD44 结合激活 CD11c^{高dMφ，从而抑制螺旋动脉重塑。}在 3 个独立的先兆子痫小鼠模型中，胎盘和血浆半乳糖凝集素 9 水平升高。小鼠中给予 Galectin-9 会诱导子痫前期样表型，伴有 CD11c^高dMφ 增加和螺旋动脉缺陷，而 Galectin-9 阻断或巨噬细胞特异性 CD44 缺失可防止此类表型。在孕妇中，妊娠早期和孕 16 至 20 周时循环半乳糖凝集素 9 水平升高可以预测随后的先兆子痫发作。结论：这些发现强调了独特的血管周围炎症性 CD11c 高^dMφ亚群在先兆子痫发病机制中的关键作用。CD11c^高dMφ 被滋养细胞中增加的半乳糖凝集素 9 激活，抑制子宫螺旋动脉重塑，导致先兆子痫。循环中半乳糖凝集素 9 的增加可能是先兆子痫预测和干预的生物标志物。