The role of placenta Hofbauer cells during pregnancy and pregnancy complications
Article information
Abstract
Placental Hofbauer cells (HBCs) are specialized macrophages present in the human placenta that play a crucial role in maintaining a healthy pregnancy. These cells are derived from the fetal mesoderm and are responsible for various functions, including immune regulation, angiogenesis, and nutrient transport. In normal pregnancies, HBCs primarily exhibit an M2 or immunomodulatory phenotype, which helps maintain a tolerant and antiinflammatory environment at the maternal-fetal interface. However, in pregnancies complicated by conditions such as immunological disorders, inflammation, or infection, the phenotype and function of HBCs may be altered. Although emerging evidence has highlighted the vital role of HBCs in both normal pregnancies and those with complications, such as chorioamnionitis, gestational diabetes, preeclampsia, and viral infections, their role remains unclear. Recent research also suggests a relationship between HBCs and the development of diseases in offspring. Understanding the role of HBCs in pregnancy could provide insights into the pathophysiology of various pregnancy-related disorders and offer potential therapeutic targets for improving maternal and fetal outcomes. This review explores the functions of HBCs in normal pregnancy and their involvement in complications, emphasizing their potential as biomarkers or targets for interventions aimed at reducing the incidence of adverse pregnancy outcomes. Additionally, we reviewed their potential for perinatal research in recent studies.
Introduction
In 1953, Sir Peter Medawar, who later won the Nobel Prize in the 1960s, published an influential essay titled ‘some immunological and endocrinological problems raised by the evolution of viviparity in vertebrates’; this work highlighted the paradoxical nature of pregnancy, focusing on the unique immunological relationship between fetal tissues and the maternal immune system [1]. Medawar’s essay significantly shaped the development of reproductive immunology and established him as a distinct founder in this field [2].
Pregnancy presents a fundamental immunological challenge due to the genetic differences between the mother and fetus, raising the question of how the maternal immune system adapts the fetus as a ‘foreign body’. Despite genetic differences, which could lead to immunological rejection, most pregnancies progress to term successfully, resulting in healthy births. However, during pregnancy, embryos/fetuses are actually “strangers on strange lands” [3]. The placenta is an essential organ that protects, develops, and grows embryos and fetuses. It facilitates the exchange of gases, nutrients, and waste products by connecting the maternal and fetal systems [4].
The placenta is primarily composed of cytotrophoblasts (CTBs) and stromal cells. Early CTB stem cells subsequently differentiate into extravillous cytotrophoblasts (EVCTs) and villous cytotrophoblasts. The villous cytotrophoblasts on floating villi differentiate into syncytiotrophoblasts (STBs), which are multinucleated cells that secrete various pregnancy hormones [5,6]. Stromal cells contain fibroblasts, such as mesenchymal stem cells, Hofbauer cells (HBCs), placental macrophages, and fetal vascular endothelial cells [4,7].
HBCs play a multifaceted role in pregnancy, including contributing to the regulation of villus trophoblast differentiation, placental angiogenesis and vasculogenesis, stromal cell growth, and the absorption of maternally derived immune complexes [7]. Understanding the role of HBCs in pregnancy could provide insights into the pathophysiology of various pregnancy-related disorders and offer potential therapeutic targets for improving maternal and fetal outcomes. This review explores the well-known functions of CTBs alongside the roles and characteristics of HBCs in normal pregnancy, pregnancy complications, and their applicability in perinatal research.
Maternal-fetal interfaces
The maternal-fetal interface is a specialized immunological site where maternal immune cells and fetal placental cells interact (Fig. 1). There are two types of immunological interfaces involved in this interaction. The first interface (interface 1), which predominates during early pregnancy, is the site of interaction between EVCTs and maternal immune cells in the decidua. Interface 1 is characterized by proper human leukocyte antigen G and killer immunoglobulin-like receptor expression on EVCTs for immune escape from maternal cells, such as cytotoxic inhibition of natural killer cells and dendritic cells [2,8-14]. Additionally, maternal macrophages at this interface tend to differentiate into the M2-like or immature phenotypes, while immune-tolerant lymphocytes such as Bregs and Treg phenotypes proliferate to support fetal tolerance [12,15-17].

Schematic diagram about two interfaces between maternal-fetal barriers: extravillous cytotrophoblast (EVCT) versus maternal decidual cell and syncytiotrophoblast (SCT) versus maternal blood (illustrated by Koonja Publishing Inc., with permission).
The second interface (interface 2) involves an interaction between the STBs of the chorionic villi and impacting maternal immune cells. It is simultaneously activated from the early first trimester (8-9 weeks of pregnancy). Interface 2 becomes dominant later in pregnancy as the placenta grows [2]. In this area, during the turnover and repair of villous CTBs and STBs, the placenta releases debris, such as syncytial knots with microparticles, into the maternal circulatory system, where they interact with circulating maternal immune cells [4,18].
Within the chorionic villi, stroma cells are located in the villous core, consisting of mesenchymal-like fibroblasts, placental macrophages (HBCs), and fetal vessels. The fetal vessel, a non-fenestrated endothelium with surrounding cells (pericytes and smooth muscle cells), lines the placental vasculature inside the villus throughout pregnancy [4]. HBCs are typically present adjacent to endothelial cords, blood vessels, and trophoblasts in situ, and their growth and function can be regulated via paracrine signaling (Fig. 2) [7,19].
Characteristics of placenta HBCs
Macrophages are associated with the initiation of innate immune responses and activation of adaptive immunity to resolve inflammation and recover affected tissue. Additionally, they play important roles in tissue development, remodeling, and homeostasis [20,21]. Since pregnancy processes, including ovulation, implantation, and delivery, involve inflammatory factors, they should be well-controlled until childbirth [22]. Uncontrolled inflammation at the maternal-placental interface can impair maternal immune tolerance and lead to fetal rejection, highlighting the necessity of regulating the inflammatory response [23].
The chorionic villi of the placenta contain prominent macrophages, known as HBCs, which are thought to originate from the fetal yolk sac [7]. These cells reside within the fetal chorionic villi of the placenta from the first trimester of pregnancy to birth and are located close to fetal vessels and trophoblasts, making them potential candidates for placental development and homeostasis [24,25]. Macrophages with phagocytic abilities are crucial in reducing placental inflammation by engulfing apoptotic bodies or necrotic debris, which may be recognized as danger-associated molecular patterns [26]. According to a simplified classification, macrophages are divided into the M1 and M2 subtypes based on their activation status [27]. Notably, the characteristics of M1-like/M2-like macrophages are similar to those of T-helper (Th)1/Th2 cells. Regarding functionality, M1 macrophages are pro-inflammatory and antimicrobial, whereas M2 macrophages are anti-inflammatory (Fig. 3) [28,29]. HBCs are classified as M2 macrophages owing to their location and anti-inflammatory role in the placenta. However, this point regarding pro-inflammatory M1 and anti-inflammatory M2 macrophages appears to be oversimplified, as HBCs can exhibit different immunophenotypes with overlapping functional properties and changes known as plasticity in response to microenvironmental stimuli [21]. HBCs are classified as a mixture of M2 macrophage polarity phenotypes, including M2a, M2b, M2c, and M2d [21,30,31], with M2b macrophages sharing similar features with M1-like macrophages [32,33]. M2 macrophage subtypes differ in various aspects, such as the expression of certain surface molecules, cytokine secretion, and function (Table 1). HBCs isolated from the human placenta at term reveal a mixture of M2a, M2b, and M2c phenotypes [34,35]. Therefore, a healthy placenta has a balanced mix of HBC subtypes that functionally compensate each other to provide an efficient environment such as vascular development, villus growth, and immune tolerance [30].

General activators and functions of M1/M2 macrophages. M1 macrophages are pro-inflammatory and antimicrobial, whereas M2 macrophages are anti-inflammatory (illustrated by Koonja Publishing Inc., with permission). IL, interleukin; IFN-γ, interferon-γ; ACAMPs, apoptotic-cell associated molecular patterns; PAMPs, pathogen-associated molecular patterns; C1q, complement component 1q; C3a, complement component 3a; C5a, complement component 5a; C3b, complement component 3b; iNOS, inducible nitric oxide synthase; TNF-α, tumor necrosis factor-α.
Role of HBCs in pregnancy
HBCs highly express cluster difference (CD) 163 and CD209 (dendritic cell-specific intercellular adhesion molecule-3-grabbing non-integrin) in the placenta. Also, HBCs highly express CD163 and CD209 (dendritic cell-specific intercellular adhesion molecule-3-grabbing non-integrin) in the placenta. Therefore, HBCs have been identified as M2 macrophages [36]. Similar to M2 macrophages, HBCs regulate angiogenesis and chorionic villus growth. The expression of vascular endothelial growth factor (VEGF) and its receptors Flt (VEGR receptor 1) and kinase insert domain receptor (KDR) (VEGF receptor 2) supports the idea that HBCs act in an autocrine fashion and are important in the early angiogenesis of the placenta in connection with the KDR receptors on endothelial cells of the fetal vessel [37,38]. HBCs also express Sprouty proteins, another family of membrane-associated proteins involved in the formation of placental villi [39]. These cells are particularly prominent in the regions of villous sprouting or growth, supporting the regulation of placental villi branching morphogenesis. Given that HBCs are present in the stromal fluid channels of villi lacking a lymphatic system, they are proposed to modulate stromal water content and ion transport through the maternal-fetal interface [7].
As immune cells, HBCs are important for preventing the vertical transmission of microorganisms from the mother to the fetus and for separating sequestered immune and complement-bound complexes from the villous core [40]. Schliefsteiner et al. [41] found that HBCs oppose bacterial cues and do not alter their M2-like phenotype despite producing tumor necrosis factor-alpha and interferon-gamma in response to bacterial pathogen-associated molecular patterns (PAMPs). However, a recent study has suggested that HBCs have varied responses to bacterial and viral PAMPs, showing phenotypic plasticity from M2-like to M1-like conversion reactions [42]. As M1 macrophage phenotypes, HBCs have cytosolic or transmembrane Toll-like receptors that recognize PAMPs and express three immunoglobulin G (IgG) Fcγ receptors, including FcγRI, FcγRII, and FcγRIII, that are the most critical Fc receptors for stimulating phagocytosis of opsonized pathogens [40]. HBCs are also involved in viral infections of the placenta, such as human immunodeficiency virus (HIV), Zika, and severe acute respiratory syndrome coronavirus 2 [43].
HBCs in pregnancy complication
Chorioamnionitis is a leading cause of preterm birth and can result in lifelong complications of prematurity in neonates. Even full-term neonates may experience sequelae of chorioamnionitis [44,45]. Various viral, bacterial, and parasitic infections can cause chorioamnionitis. Sequelae of infection during pregnancy include congenital anomalies, stillbirth, growth restriction, miscarriage, and neonatal death [46]. Several studies have suggested that morphological alterations in HBCs in placental pathologies are associated with infection, inflammation, and inadequate placental development (Table 2) [47]. Chorioamnionitis is an inflammation of the placental villi, usually triggered by TORCH infection, viral infection (HIV-1 and ZIKA virus), or other lower genital tract infections. Various studies have reported that the function of HBCs is common in chorioamnionitis. Although maternal allergen sensitization and chorioamnionitis do not affect HBC phenotype, genetic studies have reported impairments in HBC function during chorioamnionitis [48,49]. In addition, the number of CD68+ (pan-macrophage marker) HBCs decreases drastically in the presence of chorioamnionitis compared to that in healthy controls. Conversely, some studies have reported an increase in the number of CD68+ HBCs in placentas complicated by chorioamnionitis [50-52]. The primary cause of this contradictory result is likely contamination by placental macrophage preparations since 20-40% of isolated macrophages in the placenta are of maternal rather than fetal origin [53]. Therefore, the isolation of fetal-specific macrophages is key to enhancing our understanding of HBCs.
Gestational diabetes (GDM) is a pregnancy complication characterized by insulin resistance and maternal hyperglycemia. In GDM, the placenta is exposed to high blood glucose levels that induce a chronic inflammatory state of the placenta [54,55]. However, changes in the polarization pattern and function of HBCs under hyperglycemia remain unknown. Sisino et al. [56] reported that diabetes changes the normal HBC phenotype from M2 to proinflammatory M1. However, other studies have shown that HBCs maintain an M2 phenotype despite the presence of GDM, with a shift in subtype polarization toward M2a and M2b phenotypes [35,57]. These discrepancies may be due to differences in the pathogenesis and degree of inflammation induced by different severities of hyperglycemia, the duration of exposure to hyperglycemia, the identification methods of the cell population, and sample sizes [55].
Preeclampsia (PE) is characterized by maternal hypertension, placental villus prematurity, proteinuria due to glomerular damage, and preterm birth [58]. In normal placental development, low oxygen levels may also be crucial in the normal development of HBC progenitors during the first trimester because primitive embryonic hematopoiesis occurs under conditions of severe hypoxia [59]. However, in PE with an imbalance among proangiogenic (VEGF, placenta growth factor, transforming growth factor beta, etc.) and antiangiogenic (sFlt-1, etc.) factors, HBC levels and interleukin (IL)-10 secretion in placental tissue are significantly reduced [26,60]. In a recent study, HBCs in early-onset PE showed a strong shift toward M1 polarization from M2 polarization, whereas, in late-onset PE, HBCs developed a phagocytic CD209-low M2 phenotype in which the M1 pattern was not as pronounced [36]. The authors suggested that changes in polarization patterns represent various etiologies of PE because early-onset PE is related to inflammation on the placental side, whereas a maternal inflammatory response causes late-onset PE [36].
Future research of HBCs in perinatal medicine
As precursors to many tissue-resident macrophages, including HBCs, microglia, a well-known brain tissue macrophage, also originate from the fetal yolk sac [61,62]. Therefore, these cells are exposed to the same intrauterine environment, and their developmental roles have been linked to maternal-to-fetal transmission of neurotropic viruses such as Zika, cytomegalovirus, and HIV [63]. Recent studies have identified HBC as a predictive disease marker for offspring health, offering potential insights into fetal development. Batorsky et al. [63] reported a single-cell RNA-seq study that identified common changes in fetal microglial and HBCs gene expression due to maternal obesity and sex differences. They suggested that easily accessible HBCs at birth may provide insights into fetal brain microglial programs and help identify offspring vulnerable to neurodevelopmental disorders in advance [63]. Fitzgerald et al. [64] reported that the disruption of HBC function induced by preterm birth or prenatal infection could result in an increased risk of depression and cardiovascular disease in these individuals [64]. Pantazi et al. [42] demonstrated the function of HBCs against chorioamnionitis and showed sex-dependent responses of HBCs to infectious causes, primarily associated with lipid metabolism in males and cytoskeletal organization in females. Recently, regarding posttranslational modifications and subclasses of IgG activity, HBCs were shown to be a target of sialylated IgG for term and PE to induce anti-inflammatory IL-10 cytokine secretion [65,66].
Conclusion
HBCs are phenotypically and functionally activated M2 macrophages that coordinate diverse biological functions, including microbicidal activity, angiogenesis for morphogenesis, and homeostasis in the placenta. Although new evidence has emerged that HBCs may play important roles in both normal pregnancy and pregnancy complications, such as chorioamnionitis, GDM, PE, and viral infections, their role remains unclear. Recent research suggests a relationship between HBCs and offspring disease. However, the identification of HBC dysfunction biomarkers associated with various maternal conditions during pregnancy is necessary to predict maternal and infant health.
Notes
Conflict of interest
No potential conflict of interest relevant to this article was reported.
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Funding information
This work was supported by the National Research Foundation of Korea (NRF) grants funded by the Korean government (Ministry of Science and ICT, MSIT) (No. 2022R1A2C1009466 [Y.S.K], No. RS-2023-00280626 [H.S.H], and No. RS-2023-00213334 [S.W.Y]).