Deciphering the physiological function of the NLRP3 inflammasome in placentation

胎盘中母胎相互作用的紊乱与妊娠并发症有关，如宫内生长受限(IUGR)。这类妊娠并发症是常见的全球健康问题(发病率：5-7%)。尽管如此，为妊娠并发症的新治疗方法提供理论基础的机械性见解仍然很少。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有限了解。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，它反映了一种与低度炎症相关的高度特异性免疫反应。因此，胎盘含有特定的免疫细胞，特别是NK细胞(自然杀伤细胞)和某些细胞因子(如干扰素γ、IL-1β)。一些炎性小体(如NLRP2)在胎盘形成过程中的功能已经被描述。然而，研究最多的炎症体NLRP3炎症体的功能仍不清楚。这是一个相关的话题，因为妊娠并发症，如先兆子痫与NLRP3的过度激活有关，抑制NLRP3已被提议作为治疗先兆子痫的药物。在未发表的工作中，我们首次确定了NLRP3炎症小体在怀孕期间的生理功能。在胎盘发育和滋养层细胞分化过程中，NLRP3炎症体被激活。缺少NLRP3的小鼠胚胎在14.5天后生长迟缓。同时，NK细胞频率、螺旋动脉重塑、胎盘血管形成和胎盘MMP2表达减少。在妊娠合并IUGR患者中，NLRP3和MMP2的表达也同样降低。有趣的是，我们能够检测到NLRP3在人类滋养层细胞中的核表达，它与未知的核蛋白相互作用。基于这些数据，我们假设NLRP3在胎盘形成过程中通过典型的(IL-1β依赖的)和非典型的(核的NLRP3)效应来传递生理功能。具体地说，我们希望在拟议的工作中解决以下目标：1.确定NLRP3炎症小体对胎盘免疫表型的影响；2.研究NLRP3与NK细胞-滋养层细胞相互作用的相关性；3.仔细研究核NLRP3在滋养层细胞分化中的作用。

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 In unpublished work we identified for the first time a physiological function of the NLRP3 inflammasome during pregnancy.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.