小柯机器人

RANK调控妊娠疾病和流产
2020-12-25 15:03

奥地利奥地利科学院(IMBA)分子生物技术研究所Josef M. Penninger和Magdalena Paolino研究组合作取得最新进展。他们将RANK将胸腺调节性T细胞与妊娠中的流产和妊娠糖尿病联系起来。相关论文于2020年12月23日发表在《自然》杂志上。

他们显示破骨细胞分化受体RANK在怀孕期间将女性性激素与胸腺的重新布线相结合。胸腺上皮细胞中Rank(也称为Tnfrsf11a)的基因缺失导致怀孕雌性小鼠的胸腺退化受损,自然调节性T(Treg)细胞膨胀减弱。性激素,特别是孕激素,通过RANK以依赖AIRE +髓样胸腺上皮细胞的方式驱动胸腺Treg细胞的发育。小鼠胸腺上皮细胞中Rank的耗尽导致胎盘中天然Treg细胞的积累减少,流产次数增加。

胸腺Rank缺失还导致内脏脂肪组织中Treg细胞的蓄积受损,并且与脂肪细胞大小增大、组织炎症、孕产妇葡萄糖耐量增加、胎儿巨大以及葡萄糖稳态的长期持续遗传改变有关,这是妊娠糖尿病的关键标志。Treg细胞的移植可以挽救流产,孕妇的葡萄糖耐量下降和胎儿的巨大。在人类妊娠过程中,他们发现妊娠糖尿病还与胎盘中Treg细胞数量减少有关。他们的研究结果表明,RANK在怀孕期间促进了激素介导的胸腺Treg细胞的发育,并扩大了母体Treg细胞对妊娠糖尿病和葡萄糖稳态的跨代谢重建的功能作用。

研究人员表示,成功的怀孕取决于母亲的适应,包括免疫系统的明显变化。众所周知,在怀孕期间胸腺、中央淋巴器官会发生明显变化。但是,这个过程的分子基础和重要性仍然很模糊。

附:英文原文

Title: RANK links thymic regulatory T cells to fetal loss and gestational diabetes in pregnancy

Author: Magdalena Paolino, Rubina Koglgruber, Shane J. F. Cronin, Iris Uribesalgo, Esther Rauscher, Jrgen Harreiter, Michael Schuster, Dagmar Bancher-Todesca, Blanka Pranjic, Maria Novatchkova, Juan P. Fededa, Andrea J. White, Verena Sigl, Sabine Dekan, Thomas Penz, Christoph Bock, Lukas Kenner, Georg A. Hollnder, Graham Anderson, Alexandra Kautzky-Willer, Josef M. Penninger

Issue&Volume: 2020-12-23

Abstract: Successful pregnancies rely on adaptations within the mother1, including marked changes within the immune system2. It has long been known that the thymus, the central lymphoid organ, changes markedly during pregnancy3. However, the molecular basis and importance of this process remain largely obscure. Here we show that the osteoclast differentiation receptor RANK4,5 couples female sex hormones to the rewiring of the thymus during pregnancy. Genetic deletion of Rank (also known as Tnfrsf11a) in thymic epithelial cells results in impaired thymic involution and blunted expansion of natural regulatory T (Treg) cells in pregnant female mice. Sex hormones, in particular progesterone, drive the development of thymic Treg cells through RANK in a manner that depends on AIRE+ medullary thymic epithelial cells. The depletion of Rank in the mouse thymic epithelium results in reduced accumulation of natural Treg cells in the placenta, and an increase in the number of miscarriages. Thymic deletion of Rank also results in impaired accumulation of Treg cells in visceral adipose tissue, and is associated with enlarged adipocyte size, tissue inflammation, enhanced maternal glucose intolerance, fetal macrosomia, and a long-lasting transgenerational alteration in glucose homeostasis, which are all key hallmarks of gestational diabetes. Transplantation of Treg cells rescued fetal loss, maternal glucose intolerance and fetal macrosomia. In human pregnancies, we found that gestational diabetes also correlates with a reduced number of Treg cells in the placenta. Our findings show that RANK promotes the hormone-mediated development of thymic Treg cells during pregnancy, and expand the functional role of maternal Treg cells to the development of gestational diabetes and the transgenerational metabolic rewiring of glucose homeostasis. RANK promotes the hormone-mediated development of thymic regulatory T cells during pregnancy; loss of RANK is associated with impaired maturation of maternal regulatory T cells, leading to fetal loss and the development of gestational diabetes.

DOI: 10.1038/s41586-020-03071-0

Source: https://www.nature.com/articles/s41586-020-03071-0

Nature:《自然》,创刊于1869年。隶属于施普林格·自然出版集团,最新IF:69.504
官方网址:http://www.nature.com/
投稿链接:http://www.nature.com/authors/submit_manuscript.html


本期文章:《自然》:Online/在线发表

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