The Role of Macrophages in Utero-placental Interactions During Normal and Pathological Pregnancy

Abstract

The intimate association between maternal and placental tissues elicits an interesting immunological paradox. Placental tissue contains paternal antigens, but under normal circumstances the semi-allogeneic fetus and placenta are not attacked by the maternal immune system. Interestingly, this tolerance to fetal antigens occurs in the presence of a large number of maternal leukocytes, almost all of which are members of the innate immune system. Macrophages are one of the most abundant leukocytes in the decidua and their numbers remain constant throughout gestation. They are recruited to the decidua by both stromal cells and trophoblast cells, where they adopt a specialized phenotype that may assist in various aspects of decidual homeostasis, placental development, and tolerance to the semi-allogeneic trophoblast. Aberrant behavior of these macrophages can affect trophoblast function and placental development, potentially leading to a spectrum of adverse pregnancy outcomes ranging from pre-eclampsia to fetal growth restriction or demise. This review will focus on the phenotype and putative functions of decidual macrophages in normal pregnancy, and how abnormal activation of these cells can affect various aspects of placental development.

The activating effect of IFN-γ on monocytes/macrophages is regulated by the LIF–trophoblast–IL-10 axis via Stat1 inhibition and Stat3 activation

“…These cells have potential inflammatory and antigen-presenting cell functions that could be detrimental to the fetus if the cells were over-activated in response to infection. 7,8,13,14,17,22 CD14 is part of a cognate receptor complex, which includes TLR4 and myeloid differentiation factor 2 and is involved in Mw detection of Gram-negative bacteria via binding to the outer-wall component LPS. 56 IFN-c-primed Mws produced higher levels of pro-inflammatory cytokines and chemokines after stimulation with LPS via the upregulation of CD14, TLR4 and myeloid differentiation factor 2 expression.…”

“…17,18 For instance, gestational complications have been linked to elevated IFN-c and/or TNF-a expression in the immune-mediated, early abortion mouse model CBA/J3DBA/2J 17,18 and in the preterm labor and delivery model that employs LPS-treated IL-10 knockout (KO) mice. 19,20 Moreover, as observed during recurrent spontaneous abortion and intrauterine infection-associated preterm labor in humans, 7,8 aberrant inflammatory behavior in Mws is associated with spontaneous and endotoxin-mediated abortion in rodents. 21 Thus, even if a pro-inflammatory Th1 environment appears to be required for successful blastocyst implantation, 13,14 the regulation of pro-inflammatory Mw activation within the pregnant uterus may be vital to the avoidance of detrimental Mw functions, which could ultimately lead to placental and fetal demise.…”

“…7,8 However, although Mws play important roles at the maternal2fetal interface, aberrant activation of inflammatory pathways in Mws can affect trophoblast survival and function, 12 potentially leading to pregnancy complications, such as recurrent spontaneous abortion, pre-eclampsia, fetal growth restriction and intrauterine infection-associated preterm labor in humans. 7,8 Whereas gestation has long been recognized as an antiinflammatory Th2 condition, recent studies demonstrated that the process of blastocyst implantation requires a pro-inflammatory Th1 environment. 13,14 The transitory maintenance of this Th1 environment appears to be essential for the growth and survival of trophoblast cells, which in turn produce a balance of pro-and anti-inflammatory cytokines that are linked to the control of leukocyte recruitment, to the regulation of inflammatory activity, and to the promotion of Th2 immune responses.…”

“…[3][4][5][6] Tissue Mws constitute one of the most abundant populations of inflammatory cells in the uterus, and the numbers of these cells remain relatively constant in the decidua throughout gestation. 7,8 In normal pregnancies, the phenotype of uterine Mws is locally modified to acquire a type-2 phenotype, 9-11 which may contribute to trophoblast differentiation, support embryo implantation and supply growth factors to the placenta. 7,8 However, although Mws play important roles at the maternal2fetal interface, aberrant activation of inflammatory pathways in Mws can affect trophoblast survival and function, 12 potentially leading to pregnancy complications, such as recurrent spontaneous abortion, pre-eclampsia, fetal growth restriction and intrauterine infection-associated preterm labor in humans.…”

“…7,8 In normal pregnancies, the phenotype of uterine Mws is locally modified to acquire a type-2 phenotype, 9-11 which may contribute to trophoblast differentiation, support embryo implantation and supply growth factors to the placenta. 7,8 However, although Mws play important roles at the maternal2fetal interface, aberrant activation of inflammatory pathways in Mws can affect trophoblast survival and function, 12 potentially leading to pregnancy complications, such as recurrent spontaneous abortion, pre-eclampsia, fetal growth restriction and intrauterine infection-associated preterm labor in humans. 7,8 Whereas gestation has long been recognized as an antiinflammatory Th2 condition, recent studies demonstrated that the process of blastocyst implantation requires a pro-inflammatory Th1 environment.…”