Abstract
IntroductionInflammation is a normal physiological process that increases to harmful levels in preeclampsia. It affects the interaction between maternal immune cells and fetal trophoblasts at both sites of the maternal-fetal interface; decidua and placenta. The pattern recognition receptor nucleotide-binding oligomerization domain-containing protein (NOD)1 is expressed at both sites. This study aimed to characterize the cellular expression and functionality of NOD1 at the maternal-fetal interface of normal and preeclamptic pregnancies. MethodsWomen with normal or preeclamptic pregnancies delivered by caesarean section were included. Decidual (n = 90) and placental (n = 91) samples were analyzed for NOD1 expression by immunohistochemistry and an automated image-based quantification method. Decidual and placental explants were incubated with or without the NOD1-agonist iE-DAP and cytokine responses measured by ELISA. ResultsNOD1 was markedly expressed by maternal cells in the decidua and by fetal trophoblasts in both decidua and placenta, with trophoblasts showing the highest NOD1 expression. Preeclampsia with normal fetal growth was associated with a trophoblast-dependent increase in decidual NOD1 expression density. Compared to normal pregnancies, preeclampsia demonstrated stronger correlation between decidual and placental NOD1 expression levels. Increased production of interleukin (IL)-6 or IL-8 after in vitro explant stimulation confirmed NOD1 functionality. DiscussionThese findings suggest that NOD1 contributes to inflammation at the maternal-fetal interface in normal pregnancies and preeclampsia and indicate a role in direct maternal-fetal communication. The strong expression of NOD1 by all trophoblast types highlights the importance of combined assessment of decidua and placenta for overall understanding of pathophysiological processes at the maternal-fetal interface.
Highlights
Inflammation is a normal physiological process that increases to harmful levels in preeclampsia
This study demonstrated that nucleotide-binding oligomerization domain-containing protein 1 (NOD1) is strongly expressed by all types of trophoblasts across the maternal-fetal interface and moderately expressed by maternal cells in the decidua
Preeclamptic pregnancies showed stronger correlation between decidual and placental NOD1 expression, and preeclampsia with normal fetal growth was associated with a trophoblast-dependent increase in decidual NOD1 expression density
Summary
Inflammation is a normal physiological process that increases to harmful levels in preeclampsia It affects the interaction between maternal immune cells and fetal trophoblasts at both sites of the maternal-fetal interface; decidua and placenta. The multi nucleated syncytiotrophoblast layer that covers the fetal placental structures is directly exposed to immune cells in the circulating maternal blood [3] These two delicate maternal-fetal interaction sites are sensi tive to perturbations of both exogenous and endogenous origin, and untimely inflammatory triggers can induce a harmful immune activation during pregnancy [3,4]. Preeclampsia is characterized by exaggerated inflammation with increased production of inflammatory cytokines both at the maternal-fetal interface and in the maternal circulation [6,10] This harmful inflammation is associated with deficient spiral artery remodeling in the decidua and subsequent altered uteroplacental perfusion causing hemodynamic, oxidative, and endoplasmic reticulum (ER) stress in the placenta. The dysfunc tional placenta releases increasing amounts of danger signals to the maternal circulation, thereby eliciting maternal systemic inflammation, endothelial dysfunction and symptomatic preeclampsia [11,12]
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