Inflammation by pattern recognition receptors in the uterine wall decidua and the placenta of normal and preeclamptic pregnancies

Abstract

Preeclampsia is a serious inflammatory disorder characterized by hypertension and proteinuria in the second half of pregnancy. It is often associated with severe maternal and fetal complications, such as fetal growth restriction (FGR). Normal pregnancy is characterized by physiologic low-grade inflammation at the maternal-fetal interface and this inflammatory state is exaggerated to harmful levels in preeclampsia. The maternal-fetal interface comprises two sites: the decidua lining the uterine wall and the placenta consisting of fetal tissue. Specialized fetal cells, called trophoblasts, communicate with maternal cells at both sites. Optimal maternal-fetal interaction is important for proper pregnancy development and abnormal responses are associated with increased inflammation and pregnancy complications such as preeclampsia. Involvement of pattern recognition receptors (PRRs) in the inflammation at the maternal-fetal interface has been indicated, but detailed understanding of cellular expression and functionality is missing. This thesis aimed to characterize inflammatory pathways at the maternal-fetal interface and investigate involvement in the pathophysiology of preeclampsia with and without FGR. This was pursued by comprehensive characterization of three potent PRR pathways that have been associated with preeclampsia: crystal induced NLRP3 inflammasome activation; HMGB1-mediated TLR2 and TLR4 activation; and NOD1 activation. Analysis of the inflammatory pathways was performed in decidual and placental tissue and maternal blood from normal pregnancies and preeclamptic pregnancies with or without FGR. The three inflammatory pathways were expressed at the maternal-fetal interface in normal and preeclamptic pregnancies. Cholesterol crystals are potent NLRP3 ligands and were detected in the decidua in normal and preeclamptic pregnancies. A strong decidual expression of the NLRP3 inflammasome pathway and NOD1 was detected in maternal cells and trophoblasts. This expression was increased in preeclampsia with FGR in a trophoblast-dependent manner and was strongest in areas of close proximity of trophoblasts and maternal leukocytes. Preeclampsia was further associated with stronger placental trophoblast expression of the HMGB1-TLR4 and the NLRP3 inflammasome pathways. Increased maternal serum levels of the NLRP3 ligands cholesterol and uric acid and the TLR4 responsive cytokine IL-8 were observed in preeclampsia compared to normal pregnancies. Maternal serum levels of HMGB1, cholesterol and uric acid correlated with serum levels of the inflammatory marker high-sensitivity CRP and the placental dysfunction marker sFlt-1. A coordinated expression of NOD1 was observed across the maternal-fetal interface, while the NLRP3 inflammasome seemed to be differentially regulated. Functionality was demonstrated by specific ligand induced cytokine response from cultured decidual and placental tissue. Placental inflammation by TLR4 and NLRP3 was associated with preeclampsia with FGR, while decidual inflammation by NLRP3 and NOD1 was associated with preeclampsia without FGR. This thesis substantiates the role of three potent inflammatory pathways at the maternal-fetal interface in normal and preeclamptic pregnancies and suggests that they may contribute differently to the pathophysiology of preeclampsia with and without FGR. Trophoblasts were identified as central players and a pro-inflammatory profile in decidua was attributed to maternal-fetal interaction. These findings highlight the importance of studying disease mechanisms at both sites of the maternal-fetal interface.