Inflammation in Pregnancy – A Study of Pattern Recognition Receptors in Trophoblasts
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Normal pregnancy is characterized by a mildly elevated state of inflammation, as a consequence of the woman’s body adapting to the presence of the growing fetus. The placenta is established in early pregnancy, and constitutes a physical and immunological interface between the mother and the semi-foreign fetus. The principal cell type of the placenta is the fetal-derived trophoblast, which interacts with maternal immune cells to promote tolerance and create an optimal environment for the fetus in the maternal uterine compartment. Pattern recognition receptors (PRRs) are crucial in initiation of immune responses, and the discovery of such receptors in trophoblasts opened up the possibility for a more central trophoblast role in inflammatory responses at the maternal-fetal interface. PRRs recognize and bind conserved microbial components, pathogen-associated molecular patterns (PAMPs), in addition to host-derived molecules known as damage-associated molecular patterns (DAMPs), and the common downstream result of PRR-activation is production of pro-inflammatory cytokines. Three main groups of PRRs are the Toll-like receptors (TLRs), the NOD-like receptors (NLRs) and the RIG-1-like receptors (RLRs). The presence of PRRs in trophoblasts is a two-edged sword; on one hand the receptors are critically important sensors, enabling the trophoblasts to orchestrate local immune responses in the placenta. However, aberrant PRR-activation may have detrimental consequences for the pregnancy, like the inflammatory pregnancy complication pre-eclampsia. In this study, primary first trimester trophoblasts expressed all the 15 PRRs investigated, and responded to TLR activation by increased production of pro-inflammatory cytokines, particularly IL-6, IL-8 and IP-10. Both gene expression and cytokine responses varied between primary trophoblast isolates from different placentas. Cholesterol crystals, known to initiate inflammation through NLRP3-mediated induction of IL-1β, increased secretion of IL-1β in one of the four primary trophoblast isolates studied. The first trimester trophoblast cell lines BeWo and ACH-3P showed a relative broad PRR gene expression but were largely unresponsive to PRR-stimulation, indicating that extrapolating results from cell line experiments to primary trophoblasts and to in vivo situations may be misleading. The endothelial cell line HUVEC, included in this study to represent systemic inflammation, showed a more limited response to PRR-activation than the primary trophoblasts. In conclusion, this study suggests that first trimester trophoblasts can play an important role as immunomodulators in normal pregnancy, as well as contributing to the pathogenesis of inflammatory pregnancy disorders.