PDF(Pubmed)
Abstract：
Myeloid-derived suppressor cells (MDSCs) play a crucial role in maintaining maternal-fetal tolerance by expressing some immune-suppressive molecules, such as indoleamine 2,3-dioxygenase (IDO). Toxoplasma gondii (T. gondii) infection can break the immune microenvironment of maternal-fetal interface, resulting in adverse pregnancy outcomes. However, whether T. gondii affects IDO expression in dMDSCs and the molecular mechanism of its effect are still unclear. Here we show, the mRNA level of IDO is increased but the protein level decreased in infected dMDSCs. Mechanistically, the upregulation of transcriptional levels of IDO in dMDSCs is regulated through STAT3/p52-RelB pathway and the decrease of IDO expression is due to its degradation caused by increased SOCS3 after T. gondii infection. In vivo, the adverse pregnancy outcomes of IDO-/- infected mice are more severe than those of wide-type infected mice and obviously improved after exogenous kynurenine treatment. Also, the reduction of IDO in dMDSCs induced by T. gondii infection results in the downregulation of TGF-β and IL-10 expression in dNK cells regulated through Kyn/AhR/SP1 signal pathway, eventually leading to the dysfunction of dNK cells and contributing the occurrence of adverse pregnancy outcomes. This study reveals a novel molecular mechanism in adverse pregnancy outcome induced by T. gondii infection.
摘要：
髓系来源的抑制细胞（MDSCs）通过表达一些免疫抑制分子在维持母胎耐受中起着至关重要的作用。如吲哚胺2,3-双加氧酶(IDO)。弓形虫(T.gondii）感染可以破坏母胎界面的免疫微环境，导致不良妊娠结局。然而,弓形虫是否影响dMDSCs中IDO的表达及其作用的分子机制尚不清楚。在这里我们展示，在感染的dMDSCs中，IDO的mRNA水平升高，但蛋白水平降低。机械上,dMDSCs中IDO转录水平的上调是通过STAT3/p52-RelB途径调节的,而IDO表达的降低是由于弓形虫感染后SOCS3增加引起的降解。在体内,IDO-/-感染小鼠的不良妊娠结局比广型感染小鼠更为严重，经外源性犬尿氨酸治疗后明显改善。此外，弓形虫感染诱导的dMDSCs中IDO的减少导致通过Kyn/AhR/SP1信号通路调节的dNK细胞中TGF-β和IL-10的表达下调,最终导致dNK细胞功能障碍，并导致不良妊娠结局的发生。这项研究揭示了弓形虫感染引起的不良妊娠结局的新分子机制。
