Motomura Kenichiro, Morita Hideaki, Okada Naoko, Matsuda Akio, Nakae Susumu, Fujieda Mikiya, Sago Haruhiko, Saito Hirohisa, Matsumoto Kenji
Department of Allergy and Clinical Immunology, National Research Institute for Child Health and Development, Tokyo, Japan.
Center for Maternal-Fetal, Neonatal and Reproductive Medicine, National Center for Child Health and Development, Tokyo, Japan.
J Immunol. 2023 May 15;210(10):1552-1563. doi: 10.4049/jimmunol.2300008.
Pregnant women are exposed to various microbes, some of which can harm the mother and/or fetus and can lead to life-long morbidity and even death. The syncytiotrophoblast (STB) covers the placental villi and comes into direct contact with pathogens contained in the maternal blood and plays a key role in placental host defense. However, the precise mechanisms whereby the STB recognizes and responds to pathogenic microbes remain unclear. In this study, we comprehensively analyzed the expression of functional pattern recognition receptors, which are responsible for tissue defense against pathogens, in a primary STB model differentiated from highly purified human term cytotrophoblasts (CTBs). Screening for mRNA expression and multiplex cytokine/chemokine production demonstrated that differentiated CTBs (dCTBs) predominantly expressed dsRNA receptors, including TLR3, MDA5, and RIG-I. We confirmed that term human placentas also expressed TLR3. Transcriptome analysis revealed common and unique responses of dCTBs to a synthetic dsRNA (polyinosinic-polycytidylic acid) compared with human peripheral mononuclear cells. Moreover, polyinosinic-polycytidylic acid induced the release of type I and type III IFNs (IFN-β, IFN-λ1, IFN-λ2, IFN-λ3), as well as mRNA expression of IFN-stimulated genes (IFIT1, MX1, and OAS1). dCTBs underwent apoptosis via the mitochondrial pathway in response to dsRNA stimulation. These results suggest that dsRNA receptors expressed on the STB are key players in antiviral defense in the placenta. Elucidation of the underpinnings of these defense processes can help us better understand the pathophysiology of viral infections during pregnancy.
孕妇会接触到各种微生物，其中一些可能会伤害母亲和/或胎儿，并可能导致终身发病甚至死亡。合体滋养层细胞（STB）覆盖胎盘绒毛，与母体血液中所含的病原体直接接触，在胎盘宿主防御中起关键作用。然而，STB识别和应对病原微生物的确切机制仍不清楚。在本研究中，我们全面分析了功能性模式识别受体的表达，这些受体负责组织对病原体的防御，该分析是在由高度纯化的人足月细胞滋养层细胞（CTB）分化而来的原代STB模型中进行的。对mRNA表达和多种细胞因子/趋化因子产生的筛选表明，分化的CTB（dCTB）主要表达双链RNA受体，包括TLR3、MDA5和RIG-I。我们证实足月人胎盘也表达TLR3。转录组分析揭示了与人类外周血单个核细胞相比，dCTB对合成双链RNA（聚肌苷酸-聚胞苷酸）的共同和独特反应。此外，聚肌苷酸-聚胞苷酸诱导了I型和III型干扰素（IFN-β、IFN-λ1、IFN-λ2、IFN-λ3）的释放，以及干扰素刺激基因（IFIT1、MX1和OAS1）的mRNA表达。dCTB在双链RNA刺激下通过线粒体途径发生凋亡。这些结果表明，STB上表达的双链RNA受体是胎盘中抗病毒防御的关键参与者。阐明这些防御过程的基础有助于我们更好地理解孕期病毒感染的病理生理学。
