Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA.
School of Medicine, Department of Biomedical Sciences, University of Minnesota Duluth, Duluth, MN 55812, USA.
Int J Mol Sci. 2023 Sep 2;24(17):13594. doi: 10.3390/ijms241713594.
Preeclampsia is the leading cause of maternal-fetal morbidity worldwide. The concept that persistent feto-placental intolerance is important in the pathogenesis of preeclampsia (PreE) has been demonstrated by our lab and others. Arginine vasopressin (AVP) infusion during pregnancy induces cardiovascular, renal, and T helper (T) cell alterations in mice consistent with human PreE. In addition to their conventional immuno-stimulatory role, dendritic cells (DCs) also play a vital role in immune tolerance. In contrast to conventional DCs, regulatory DCs (DCregs) express low levels of co-stimulatory markers, produce anti-inflammatory cytokines, induce T regulatory (Treg) cells, and promote tolerance. In mice, DCregs prevent pro-inflammatory responses and induce antigen-specific tolerance. Given these known functions of DCregs, we hypothesize that DCregs will prevent the development of AVP-induced PreE in mice. females were infused with AVP (24 ng/h) or saline throughout gestation via an osmotic minipump. Bone-marrow-derived DCregs were injected into AVP-infused dams at the time of the pump implantation or on gestational day (GD) 7. The blood pressure of the mice was taken throughout their pregnancy. The maternal urine proteins and T-associated cytokines in maternal and fetal tissues were measured on GD 18. The treatment with DCregs effectively prevented the elevation of maternal blood pressure, proteinuria, and fetal growth restriction that were observed in AVP-infused dams. Furthermore, we noted a reduction in the pro-inflammatory T-associated cytokines IFNγ and IL-17, while anti-inflammatory cytokines IL-4, IL-10, and TGFβ showed an increase following DCreg treatment. These outcomes provide strong evidence supporting the potential of DCregs as a valuable therapeutic approach in addressing PreE.
子痫前期是全球孕产妇发病率和围产儿发病率升高的主要原因。我们实验室和其他实验室已经证明，持续性胎儿胎盘不耐受在子痫前期（PreE）的发病机制中很重要。在妊娠期间输注精氨酸加压素（AVP）会导致小鼠心血管、肾脏和 T 辅助（T）细胞发生改变，这些改变与人类 PreE 一致。树突状细胞（DCs）除了具有传统的免疫刺激作用外，还在免疫耐受中发挥着重要作用。与传统的 DC 不同，调节性 DC（DCregs）表达低水平的共刺激标志物，产生抗炎细胞因子，诱导 T 调节（Treg）细胞，并促进耐受。在小鼠中，DCregs 可防止促炎反应并诱导抗原特异性耐受。鉴于 DCregs 的这些已知功能，我们假设 DCregs 将预防 AVP 诱导的小鼠 PreE 的发生。将雌性小鼠通过渗透型微量渗透泵持续输注 AVP（24ng/h）或生理盐水直至妊娠结束。在泵植入或妊娠第 7 天（GD）时，将骨髓来源的 DCregs 注入 AVP 输注的母鼠体内。在整个妊娠期间测量小鼠的血压。在 GD 18 时测量母鼠和胎鼠组织中的尿蛋白和 T 相关细胞因子。DCregs 的治疗有效预防了 AVP 输注母鼠血压升高、蛋白尿和胎儿生长受限。此外，我们注意到促炎 T 相关细胞因子 IFNγ和 IL-17 的减少，而抗炎细胞因子 IL-4、IL-10 和 TGFβ在 DCreg 治疗后增加。这些结果为 DCregs 作为治疗 PreE 的有价值的治疗方法提供了有力的证据。
