REVIEW ARTICLE: The Contribution of Macrophages to Normal and Pathological Pregnancies

Abstract

Macrophages represent one of the major leukocyte subsets in the uterine decidua. Owing to their remarkable phenotypic plasticity, decidual macrophages can participate in diverse activities during pregnancy. At baseline, decidual macrophages are characterized by an immunosuppressive phenotype and M2 polarization, supporting feto-maternal immune tolerance. In early pregnancy, macrophage-derived pro-angiogenic factors prompt vascular remodeling within the uterine wall to ensure appropriate utero-placental circulation. Upon invasion by pathogens, pattern recognition receptors on decidual macrophages help to alter the characteristics of these malleable cells toward an M1, inflammatory phenotype. Similar inflammatory characteristics are seen in those macrophages that accumulate in the lower segment of the uterus to drive cervical ripening. Disturbances in the tight control that balances macrophage function during pregnancy can trigger the development of pregnancy complications. Here, we discuss the physiologic role of uterine macrophages at different stages of pregnancy and describe their relevance in selected pregnancy disorders.

The CXCL12/CXCR4 axis is involved in the maintenance of Th2 bias at the maternal/fetal interface in early human pregnancy

“…16 Decidual macrophages are characterized by an immunosuppressive phenotype (M2), and M2 polarization results in immune tolerance. 17,18 DSCs are the major cellular component in decidua. In addition to secreting a series of cytokines, DSCs play a crucial role as nonprofessional antigen-presenting cells in the regulation of decidual CD4 1 T-cell cytokine production which helps to maintain a balanced cytokine milieu at the maternal/fetal interface.…”

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

“…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.…”

Role of PD1/PDL1 pathway, and TH17 and treg cells in maternal tolerance to the fetus

“…Dendritic cells (DCs), [49,50] macrophages, [51] and uterine NK [52] cells are all involved in this complex regulation of tolerance. Current evidence suggests that Tregs also play an important role in this phenomenon, both in the periphery as well as locally at the FMI.…”