RANK調控妊娠疾病和流產
作者：
小柯機器人發布時間：2020/12/25 15:03:11
奧地利奧地利科學院（IMBA）分子生物技術研究所Josef M. Penninger和Magdalena Paolino研究組合作取得最新進展。他們將RANK將胸腺調節性T細胞與妊娠中的流產和妊娠糖尿病聯繫起來。相關論文於2020年12月23日發表在《自然》雜誌上。
他們顯示破骨細胞分化受體RANK在懷孕期間將女性性激素與胸腺的重新布線相結合。胸腺上皮細胞中Rank（也稱為Tnfrsf11a）的基因缺失導致懷孕雌性小鼠的胸腺退化受損，自然調節性T（Treg）細胞膨脹減弱。性激素，特別是孕激素，通過RANK以依賴AIRE +髓樣胸腺上皮細胞的方式驅動胸腺Treg細胞的發育。小鼠胸腺上皮細胞中Rank的耗盡導致胎盤中天然Treg細胞的積累減少，流產次數增加。
胸腺Rank缺失還導致內臟脂肪組織中Treg細胞的蓄積受損，並且與脂肪細胞大小增大、組織炎症、孕產婦葡萄糖耐量增加、胎兒巨大以及葡萄糖穩態的長期持續遺傳改變有關，這是妊娠糖尿病的關鍵標誌。Treg細胞的移植可以挽救流產，孕婦的葡萄糖耐量下降和胎兒的巨大。在人類妊娠過程中，他們發現妊娠糖尿病還與胎盤中Treg細胞數量減少有關。他們的研究結果表明，RANK在懷孕期間促進了激素介導的胸腺Treg細胞的發育，並擴大了母體Treg細胞對妊娠糖尿病和葡萄糖穩態的跨代謝重建的功能作用。
研究人員表示，成功的懷孕取決於母親的適應，包括免疫系統的明顯變化。眾所周知，在懷孕期間胸腺、中央淋巴器官會發生明顯變化。但是，這個過程的分子基礎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