Deciphering the physiological function of the NLRP3 inflammasome in placentation

破译 NLRP3 炎症小体在胎盘形成中的生理功能

• 批准号: 436586934
• 负责人: Professor Dr. Berend Isermann
• 金额: --
• 依托单位: Institut für Laboratoriumsmedizin, Klinische Chemie und Molekulare Diagnostik
• 依托单位国家: 德国
• 项目类别: Research Grants
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/436586934?language=en
• 关键词: Deciphering; physiological; function; NLRP3; inflammasome

Disturbances of the maternal-fetal interaction in the placenta are associated with pregnancy complications such as intra-uterine growth restriction (IUGR). Such pregnancy complications are frequent global health problems (incidence: 5–7%). Nonetheless, mechanistic insights providing a rationale for novel therapeutic approaches to pregnancy complications remain scarce. This scarcity reflects the limited understanding of the physiological mechanism regulating the maternal-fetal interaction in the placenta.Pregnancy is characterized by immune tolerance. The latter is not simply an inhibition of the immune system. Rather, it reflects a highly specific immunological reaction associated with low grade inflammation. Thus, the placenta contains specific immune cells, in particular NK cells (natural killer cells), and certain cytokines (e.g. INFγ, IL-1β). A function for some inflammasomes (e.g. NLRP2) during placentation has been described. However, a function of the otherwise most-studied inflammasome, the NLRP3 inflammasome, remains unknown. This is a relevant topic as pregnancy complications such as pre-eclampsia are associated with excess NLRP3 activation and its inhibition has been proposed as a medical remedy of pre-eclampsia. In unpublished work we identified for the first time a physiological function of the NLRP3 inflammasome during pregnancy. During placental development and trophoblast differentiation the NLRP3 inflammasome is activated. Mouse embryos lacking NLRP3 are growth retarded after day 14.5 p.c. In parallel, NK cell frequency, spiral artery remodeling, placental vascularization, and placental MMP2 expression are reduced. In human pregnancy complicated by IUGR expression of NLRP3 and MMP2 are likewise reduced. Intriguingly, we were able to detect nuclear NLRP3 expression in human trophoblast cells, which interacts with uncharacterized nuclear proteins. Based on these data we hypothesize that NLRP3 conveys a physiological function during placentation through both canonical (IL-1β dependent) and non-canonical (nuclear NLRP3) effects. In detail, we wish to address the following aims in the proposed work: 1. Determine the effect of the NLRP3 inflammasome on the placenta immunophenotype;2. Study the relevance of NLRP3 for the NK cell-trophoblast interaction; 3. Scrutinize the role of nuclear NLRP3 in trophoblast differentiation.

胎盘中母胎相互作用的紊乱与妊娠并发症如宫内生长受限（IUGR）有关。这类妊娠并发症是常见的全球健康问题（发生率：5-7%）。尽管如此，机制的见解提供了一个新的治疗方法，妊娠并发症的理由仍然很少。这种缺乏反映了对调节胎盘中母胎相互作用的生理机制的认识有限。妊娠的特征是免疫耐受。后者不仅仅是对免疫系统的抑制。相反，它反映了与低度炎症相关的高度特异性免疫反应。因此，胎盘含有特异性免疫细胞，特别是NK细胞（自然杀伤细胞）和某些细胞因子（例如INFγ，IL-1β）。已经描述了一些炎性小体（例如NLRP 2）在胎盘形成期间的功能。然而，研究最多的炎性小体NLRP 3炎性小体的功能仍然未知。这是一个相关的主题，因为妊娠并发症如先兆子痫与过量的NLRP 3活化相关，并且其抑制已被提议作为先兆子痫的医学补救。在未发表的工作中，我们首次确定了NLRP 3炎性体在妊娠期间的生理功能。在胎盘发育和滋养层分化过程中，NLRP 3炎性体被激活。缺乏NLRP 3的小鼠胚胎在交配后14.5天后生长迟缓。同时，NK细胞频率、螺旋动脉重塑、胎盘血管化和胎盘MMP 2表达降低。在伴有IUGR的人类妊娠中，NLRP 3和MMP 2的表达同样减少。有趣的是，我们能够检测到人类滋养层细胞中的核NLRP 3表达，其与未表征的核蛋白相互作用。基于这些数据，我们假设NLRP 3在胎盘形成期间通过经典（IL-1β依赖性）和非经典（核NLRP 3）效应传递生理功能。具体而言，我们希望在拟议的工作中解决以下目标：1。 确定NLRP 3炎性体对胎盘免疫表型的影响;2. 研究NLRP 3与NK细胞-滋养层细胞相互作用的相关性; 3. 核NLRP 3在滋养细胞分化中的作用。