N.N. Blokhin National Medical Research Center of Oncology, Ministry of Health of the Russian Federation, 24 Kashirskoe Shosse, Moscow 115478, Russia.
Department of Embryology, Faculty of Biology, Moscow State University, 1/12 Leninskie Gory, Moscow 119992, Russia.
Int J Mol Sci. 2023 Jul 10;24(14):11279. doi: 10.3390/ijms241411279.
The precise balance of Th1, Th2, and Th17 cytokines is a key factor in successful pregnancy and normal embryonic development. However, to date, not all humoral factors that regulate and influence physiological pregnancy have been completely studied. Our data here pointed out cyclophilin A (CypA) as the adverse pro-inflammatory factor negatively affecting fetal development and associated with pregnancy complications. In different mouse models in vivo, we demonstrated dramatic embryotoxicity and teratogenicity of increased CypA levels during pregnancy. Using generated transgenic models, we showed that CypA overexpression in fetal tissues induced the death of all transgenic fetuses and complete miscarriage. Administration of recombinant human CypA in a high dose to pregnant females during fetal organogenesis (6.5-11.5 dpc) exhibited teratogenic effects, causing severe defects in the brain and bone development that could lead to malformations and postnatal behavioral and cognitive disorders in the offspring. Embryotoxic and teratogenic effects could be mediated by CypA-induced up-regulation of M1 macrophage polarization via activation of the STAT1/3 signaling pathways. Here, we propose secreted CypA as a novel marker of complicated pregnancy and a therapeutic target for the correction of pregnancy complications.
Th1、Th2 和 Th17 细胞因子的精确平衡是成功妊娠和正常胚胎发育的关键因素。然而，迄今为止，并非所有调节和影响生理妊娠的体液因子都得到了完全研究。我们这里的数据指出亲环素 A（CypA）是一种不良的促炎因子，可对胎儿发育产生负面影响，并与妊娠并发症有关。在体内的不同小鼠模型中，我们证明了 CypA 水平升高在妊娠期间具有明显的胚胎毒性和致畸性。使用生成的转基因模型，我们表明胎儿组织中 CypA 的过表达诱导所有转基因胎儿死亡和完全流产。在胎儿器官发生期间（6.5-11.5 dpc），给怀孕母体高剂量施用重组人 CypA 表现出致畸作用，导致大脑和骨骼发育的严重缺陷，可能导致后代出现畸形和出生后行为和认知障碍。胚胎毒性和致畸作用可通过 CypA 诱导的 M1 巨噬细胞极化的上调来介导，这是通过激活 STAT1/3 信号通路实现的。在这里，我们提出分泌型 CypA 作为复杂妊娠的新型标志物和用于纠正妊娠并发症的治疗靶标。
