Decidual macrophages and Hofbauer cells in fetal growth restriction

Abstract

Placental macrophages, which include maternal decidual macrophages and fetal Hofbauer cells, display a high degree of phenotypical and functional plasticity. This provides these macrophages with a key role in immunologically driven events in pregnancy like host defense, establishing and maintaining maternal-fetal tolerance. Moreover, placental macrophages have an important role in placental development, including implantation of the conceptus and remodeling of the intrauterine vasculature. To facilitate these processes, it is crucial that placental macrophages adapt accordingly to the needs of each phase of pregnancy. Dysregulated functionalities of placental macrophages are related to placental malfunctioning and have been associated with several adverse pregnancy outcomes. Although fetal growth restriction is specifically associated with placental insufficiency, knowledge on the role of macrophages in fetal growth restriction remains limited. This review provides an overview of the distinct functionalities of decidual macrophages and Hofbauer cells in each trimester of a healthy pregnancy and aims to elucidate the mechanisms by which placental macrophages could be involved in the pathogenesis of fetal growth restriction. Additionally, potential immune targeted therapies for fetal growth restriction are discussed.

Keywords: Hofbauer cell; decidual macrophage; fetal growth restriction; maternal-fetal tolerance; placental development.

Figure 1

Overview of maternal-fetal interface. The fetal part of the placenta consists of the chorionic plate, amniotic membrane and villi. The cytotrophoblast forms the inner layer of the villi and is surrounded by a continuous outer layer of syncytiotrophoblast. Syncytiotrophoblast cells invade the endometrium during implantation of the conceptus. Extravillous trophoblast invades the maternal spiral arteries to facilitate remodeling of the vasculature. The maternal part of the placenta is formed by the decidua, which is attached to the myometrium, a layer of uterine smooth muscle cells. Blood from the maternal spiral arteries flows into the intervillous space where exchange of oxygen, nutrients and waste between mother and fetus takes place. Created with BioRender.com.

Figure 2

Hypothesis on the immunological etiology of FGR. The hypothesis encompasses a vicious circle of failed-maternal fetal tolerance, placental maldevelopment, oxidative stress and a placental inflammatory immune response. All factors in the cycle influence one another bidirectionally, ultimately causing placental insufficiency, which lies at the root of FGR. Created with BioRender.com.

Figure 3

Characteristics and functionalities of decidual macrophages. A simplified classification divides decidual macrophages in M1 and M2 subsets. Polarization factors, cell surface markers and cytokine and chemokines are shown for each subset. Ang, angiotensin; CCL, chemokine (CC-motif) ligand; CD, cluster of differentiation; CXCL, chemokine (CXC-motif) ligand; GM-CSF, growth macrophage colony stimulating factor; HLA, human leukocyte antigen; IDO, indoleamine 2,3-dioxygenase; IFN, interferon; IL, interleukin; LPS, lipopolysaccharide; M-CSF, macrophage colony stimulating factor; MMP, metalloproteinase; PlGF, placental growth factor; sFLT, soluble fms-like tyrosine kinase; TGF, tumor growth factor; TLR, toll like receptor; TNF, tumor necrosis factor; VEGF, vascular endothelial growth factor. Created with BioRender.com.

Figure 4

Characteristics and functionalities of Hofbauer cells. A simplified classification divides Hofbauer cells in M2a, M2b, M2c and M2d subsets. Polarization factors, cell surface markers and cytokine and chemokines are shown for each subset. Arg, arginase; CCL, CD, cluster of differentiation; HLA, human leukocyte antigen; IL, interleukin; M-CSF, macrophage colony stimulating factor; MMP, metalloproteinase; TGF, tumor growth factor; TNF, tumor necrosis factor; VEGF, vascular endothelial growth factor. Created with BioRender.com.

Figure 5

Summary of dMφs and HBCs in healthy pregnancies and FGR. (A) Implantation in healthy pregnancies: EVT and dMφs crosstalk facilitates deep invasion of EVT in endometrial stroma for implantation of the embryo. (B) Implantation in FGR: excess of inflammatory dMφs and EVT apoptosis, leading to shallow implantation of the embryo. (C) Vascular remodeling in healthy pregnancies: dMφs and HBCs cause disruption of VSCM and EC within maternal SA and stimulate EVT invasion, which causes remodeling of the SA into dilated, low-resistance vessels. (D) Vascular remodeling in FGR: excess of inflammatory (foamy) dMφs causes apoptosis of EVTs, leading to restricted EVT invasion. Disruption of the VSCM and EC layers is incomplete and the lumen of the SA remains narrow. (E) Tolerance and homeostasis in healthy pregnancies: dMφs and HBCs secrete anti-inflammatory cytokines and vascular growth factors, phagocytose placental debris and anti-fetal antibodies, and induce Treg cells while inhibiting potential inflammatory T cell and NK cell responses. (F) Tolerance and homeostasis in FGR: balance shifted towards dMφs and HBCs that secrete pro-inflammatory cytokines, lack vascular growth factors, and stimulate T cells and NK cells, leading to an inflammatory and hypoxic environment with impaired placental vascularization and damage to the villi. Created with BioRender.com.