Deciphering the physiological function of the NLRP3 inflammasome in placentation

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 In unpublished work we identified for the first time a physiological function of the NLRP3 inflammasome during pregnancy.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