Cui Wen, Wang Cong, Luo Qingli, Xing Tian, Shen Jilong, Wang Wei
Department of Pathogen Biology, Provincial Laboratories of Pathogen Biology and Zoonoses Anhui, School of Basic Medicine, Anhui Medical University, Hefei, China.
Department of Clinical Laboratory, The Second Hospital of Hefei, Hefei, China.
Front Microbiol. 2020 Jan 31;10:3151. doi: 10.3389/fmicb.2019.03151. eCollection 2019.
Imbalance of Th1 and Th2 response at the maternal-fetal interface is considered as a radical event in the pathogenesis of immunity-related pregnant diseases. It has been demonstrated that the ROP16, a rhoptry protein of , and the viable parasite with ROP16 may induce M2 macrophage polarization in host innate immunity and may be involved in the adverse pregnant outcomes. However, the mechanisms by which -derived effectors subvert the immune tolerance in the pathology of pregnancy remain unclear. Here, we constructed the RH strain with ROP16 deletion (RHΔ) to explore the pathogenesis of abnormal pregnancy. We found that C57BL/6 mice infected with RHΔ exhibited the increased resorption of fetuses and more severe adverse pathology of placentae at the early phase of gestation, as compared to the mice infected with RH wild type (RH WT) parasite. Additionally, RHΔ strain infection significantly promoted M1 macrophage phenotypes of CD80 and CD86, and decreased CD206 expression of M2 macrophages, with upregulation of the iNOS and downregulation of the Arg-1 expression in placental homogenates. Simultaneously, the pro-inflammatory cytokines of IL-12 and TNF-α were elevated whereas the anti-inflammatory cytokine of TGF-β1 was dampened. Moreover, the p38α mitogen-activated protein kinase (p38α MAPK) was notably phosphorylated in placental macrophages infected with both RHΔ and RH WT strains compared with the control. Taken together, our findings indicated that ROP16 deletion of type I RH strain may cause exacerbated adverse pregnant outcomes, which is attributable to subversion of the maternal immune tolerance due to the increased pro-inflammatory cytokines in the pregnant animals. The results also suggest that ROP16 might be a protective factor and other -derived molecules might be involved in the M1-Th1 biased pathological process in aberrant pregnancy at the early phase of gestation.
母胎界面处Th1和Th2反应失衡被认为是免疫相关性妊娠疾病发病机制中的一个关键事件。已有研究表明，疟原虫的一种棒状体蛋白ROP16以及携带ROP16的活寄生虫可诱导宿主固有免疫中的M2巨噬细胞极化，并可能与不良妊娠结局有关。然而，疟原虫衍生的效应分子在妊娠病理过程中破坏免疫耐受的机制仍不清楚。在此，我们构建了ROP16缺失的RH株（RHΔ）以探究异常妊娠的发病机制。我们发现，与感染RH野生型（RH WT）寄生虫的小鼠相比，感染RHΔ的C57BL/6小鼠在妊娠早期出现胎儿吸收增加以及胎盘更严重的不良病理变化。此外，RHΔ株感染显著促进了CD80和CD86的M1巨噬细胞表型，降低了M2巨噬细胞的CD206表达，同时胎盘匀浆中诱导型一氧化氮合酶（iNOS）表达上调，精氨酸酶-1（Arg-1）表达下调。同时，促炎细胞因子白细胞介素-12（IL-12）和肿瘤坏死因子-α（TNF-α）升高，而抗炎细胞因子转化生长因子-β1（TGF-β1）受到抑制。此外，与对照组相比，感染RHΔ和RH WT株的胎盘巨噬细胞中p38α丝裂原活化蛋白激酶（p38α MAPK）显著磷酸化。综上所述，我们的研究结果表明，I型RH株的ROP16缺失可能导致不良妊娠结局加剧，这归因于妊娠动物体内促炎细胞因子增加导致的母体免疫耐受破坏。结果还表明，ROP16可能是一个保护因子，其他疟原虫衍生分子可能参与了妊娠早期异常妊娠中M1-Th1偏向的病理过程。
