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

总结/摘要 怀孕对母胎免疫界面来说是一个独特的挑战，需要平衡 维持半同种异体胎儿所必需的免疫抑制和促炎性 保护母亲和胎儿免受入侵生物的宿主防御。适应反复炎症 刺激可能是关键，在防止胎儿排斥反应的夸大母体炎症反应， 到人类怀孕期间常见的轻度/中度感染。 免疫耐受/适应是一种充分描述的现象，其中细胞暴露于重复的免疫耐受/适应。 病原体对随后的接触反应会降低。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 保护性的对反复感染的免疫反应减弱与预防 在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 重复感染的背景下，人类怀孕，以及确切的机制，有助于 建立这种免疫适应以预防炎症诱导病理性妊娠并不 探讨了现在有广泛的证据表明，miRNAs在维持健康的细胞中起着重要的作用。 妊娠，与子宫内膜容受性、着床、妊娠组织有关的各种miRNA 功能和劳动力。我们的初步结果表明，重复的LPS（革兰氏阴性细菌毒素）或LTA （革兰氏阳性细菌毒素）暴露于人胎盘可减弱过度的炎症反应 已知会导致炎症相关的病理性妊娠。我们的数据还表明 一种人类和胎盘特异性的miRNA-519 c-3 p（miR-519 c）在胎盘发育中的作用 免疫耐受我们最重要的假设是，胎盘反复暴露于病原体会诱导 由miR-519 c介导的耐受表型，以保护母胎界面免受过度的 与病理性妊娠有关的炎症。我们假设LPS/LTA诱导胎盘 滋养层细胞分泌包装在胎盘细胞外囊泡内的miR-519 c，用于递送到附近或 遥远的细胞EV内的miR-519 c将介导过度的促炎性细胞因子的下调。 与反复接触细菌毒素有关的反应。 我们提出以下具体目的：目的1：研究miR-519 c在介导免疫应答中的作用。 目的2：探讨胎盘反复感染后的适应性变化及其分子机制 胎盘miR-519 c介导的免疫适应。这些研究将为未来的实验奠定基础， 检测miR-519 c表达降低是否与炎症相关的病理性妊娠有关。这 独特的人类和胎盘特异性miR-519 c可以是一种极好的生物标志物候选物， 妊娠炎性疾病的治疗靶点。

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.