Placenta-specific miR-519c-mediated induction of immune tolerance in human placenta

摘要/摘要 怀孕是母胎免疫接口的独特挑战，需要平衡 在维持半异基因胎儿所必需的免疫抑制和促炎之间 宿主防御，以保护母亲和胎儿免受生物入侵。对反复发炎的适应 刺激可能在防止母体过度炎症反应引起的排异反应中起关键作用。 到人类怀孕期间常见的轻度/中度感染。 免疫耐受/适应是一种众所周知的现象，在这种现象中，细胞暴露在重复的 病原体对随后的暴露变得不太敏感。这种适应抑制了过度的 对反复感染的侵袭性炎症反应，可能对组织有害，而不是 防护性的。对反复感染的免疫反应受抑与预防 几种人类疾病中的组织损伤和死亡率。然而，到目前为止，免疫耐受对 在人类怀孕的背景下反复感染，以及导致 建立这种免疫适应来预防炎症诱导的病理性妊娠并不是 探索过了。现在有广泛的证据表明miRNAs在维持健康的 妊娠与子宫内膜容受性、着床、妊娠组织中广泛的miRNAs有关 功能，和劳动。我们的初步结果表明，反复的内毒素(革兰氏阴性细菌毒素)或LTA (革兰氏阳性细菌毒素)暴露于人胎盘可减轻夸大的炎症反应 已知会导致炎症相关的病理性妊娠。我们的数据还表明 人和胎盘特异性miRNA miRNA-519c-3p(miR-519c)在胎盘发育中的作用 免疫耐受。我们最重要的假设是，胎盘反复暴露在病原体下会导致 MiR-519c介导的耐受表型保护母胎界面免受夸大 与病理妊娠相关的炎症。我们假设脂多糖/LTA诱导胎盘 滋养层细胞分泌包装在胎盘细胞外小泡内的miR-519c，以便运送到附近或 遥远的手机。电动汽车内的mir-519c将调节对夸张的促炎作用的下调。 与反复接触细菌毒素相关的反应。 我们提出以下具体目标：目标1：研究miR-519c在介导免疫中的作用 人胎盘反复感染后的适应性及目标2：探讨其分子机制 胎盘miR-519c介导免疫适应。这些研究将为未来的实验奠定基础 检测miR-519c的低表达是否与炎症相关的病理妊娠有关。这 独特的人类和胎盘特异性miR-519c可以作为一个很好的候选生物标记物以及 妊娠炎症性疾病的治疗靶点。

SUMMARY/ABSTRACT Pregnancy represents a unique challenge for the maternal-fetal immune interface, requiring the balance between immunosuppression, essential for the maintenance of semi-allogeneic fetus and pro-inflammatory host defense to protect the mother and fetus from invading organisms. Adaptation to repeated inflammatory stimuli may be critical in preventing rejection of the fetus by the exaggerated maternal inflammatory responses to mild/moderate infections that are common during human pregnancy. Immune tolerance/adaptation is a well-described phenomenon in which cells exposed to repeated pathogens become less responsive to subsequent exposures. This adaptation suppresses an overly aggressive inflammatory response to repeated infections that can be detrimental to the tissues rather than protective. Dampened immune response to repeated infections has been associated with protection against tissue injury and mortality in several human diseases. However, to date, the role of immune tolerance to repeated infections in the context of human pregnancy, and the exact mechanisms that contribute to the establishment of such immune adaptation to prevent inflammation-induced pathologic pregnancies are not explored. There is now extensive evidence that miRNAs play an important role in the maintenance of a healthy pregnancy, with a wide range of miRNAs implicated in endometrial receptivity, implantation, gestational tissues function, and labor. Our preliminary results indicate that repeated LPS (gram negative bacterial toxins) or LTA (gram-positive bacterial toxins) exposures to human placenta attenuates exaggerated inflammatory responses known to contribute to inflammation-associated pathologic pregnancies. Our data also point to the involvement of a human- and placenta-specific miRNA called miRNA-519c-3p (miR-519c) in the development of placental immune tolerance. Our overriding hypothesis is that repeated exposure of the placenta to pathogens induces a tolerant phenotype mediated by the miR-519c to guard the maternal-fetal interface from the exaggerated inflammation associated with pathologic pregnancies. We hypothesize that LPS/LTA induce placental trophoblasts to secrete miR-519c packaged within placental extracellular vesicles for delivery to nearby or distant cells. The miR-519c within the EVs will mediate down-regulation of exaggerated pro-inflammatory responses associated with repeated bacterial toxin exposures. We propose the following specific aims: Aim 1: Investigate the role of miR-519c in mediating immune adaptation in the human placenta after repeated infections and Aim 2: Investigate the molecular mechanisms of placental miR-519c mediating immune adaptation. These studies will set the stage for future experiments to test if decreased expression of miR-519c is linked to inflammation-associated pathologic pregnancies. This unique human- and placenta-specific miR-519c can be an excellent biomarker candidate as well as a therapeutic target for inflammatory diseases of pregnancy.