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Obstet Gynecol Sci > Volume 68(1); 2025 > Article
Yang, Hwang, and Kang: The role of placenta Hofbauer cells during pregnancy and pregnancy complications

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].
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].

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.

Ethical approval

Not applicable.

Patient consent

No patient consent is needed for this review article.

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]).

Fig. 1.
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).
ogs-24247f1.jpg
Fig. 2.
Schematic diagram about human floating chorionic villi. Inside the chorionic villi, stroma cells (fibroblasts, Hofbauer cells, and fetal endothelial cells) are located in the villous core (illustrated by Koonja Publishing Inc., with permission).
ogs-24247f2.jpg
Fig. 3.
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.
ogs-24247f3.jpg
Table 1.
General feature of macrophage polarity for HBC [21,30]
M1 M2a M2b M2c M2d
Stimulus IFN-γ+LPS IL-4 Immune complexes IL-10 IL-6
IFN-γ+TNF IL-13 IL-1R TGF-β LIF
GM-CSF Fungal and parasitic Glucocorticoids M-CSF
Infections Adenosine
Cell surface molecule/markers CD16 CD163 CD86 CD163 CD163
CD32 IL-1R MHCII TLR1 CD14
CD64 MHCIIlow TLR8 CD85
CD80/86 CD206 CD206
HLA-DR IL-RN CD14
CD 209 (DC-SIGN)
Secreted cytokine TNF-α IL-10 IL-1β IL-10 VEGF
IL-1β TGF-β1 IL-6 TGF-β MMP-9
IFN-γ IL-1RA IL-10 IDO
IL-6 IL-13 TNF-α IL-10
IL-12 IL-12low
IL-23 TNF-αlow
Type I interferons TGF-β
Secreted chemokine CCL10 CCL17 CCL1 CXCL13 CCL5
CCL11 CCL18 CCL20 CCR2 CXCL10
CCL5 CCL22 Pentraxin3 CXCL16
CCL8
CCL9
CCL2
CCL3
CCL4
Function/pathology TH1 responses TH2 responses TH2 activation Immune regulation Immune suppression
Killing intracellular pathogens Anti-inflammatory Immune regulation Tissue repair/wound healing Angiogenesis
Pro-inflammatory Wound healing Phagocytosis of apoptotic cells Tissue remodeling
Antigen presentation Anti-inflammatory
Tissue damage

HBC, Hofbauer cells; IFN, interferon; LPS, lipopolysaccharide; TNF, tumor necrosis factor; GM-CSF, granulocyte-macrophage colony-stimulating factor; IL, interlekin; IL1R, interleukin 1 receptor; TGF, transforming growth factor; LIF, leukemia inhibitory factor; M-CSF, macrophage colonystimulating factor; CD, cluster difference; HLA-DR, human leukocyte antigen-DR; MHCII, major histocompatibility complex II; DC-SIGN, dendritic cell-specific intercellular adhesion molecule-3-grabbing non-integrin; TLR, toll-like receptor; IL-1RA, interleukin-1 receptor antagonist; VEGF, vascular endothelial growth factor; MMP, matrix metalloproteinase; IDO, indoleamine 2,3-dioxygenase; CCL, chemokine ligand; CXCL, chemokine (C-X-C motif) ligand; CCR, chemokine receptor; TH, T helper cell.

Table 2.
HBC hyperplasia and infection by common pregnancyrelated pathogens [47]
Hyperplasia
 Parvovirus
Troponema pallidum
Infection
 HIV-1
 HSV
 H5N1
 HPV
 RSV
 Enterovirus
Hyperplasia and infection
 ZIKA
 CMV
 SARS-CoV-2
 DENV
 Coxsackie virus

HBC, hofbauer cells; HIV, human immunodeficiency virus; HSV, herpes simplex virus; H5N1, influenza virus A; HPV, human papillomavirus; RSV, respiratory syncytial virus; ZIKA, ZIKA virus; CMV, cytomegalovirus; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; DENV, dengue virus.

References

1. Medawar PB. Some immunological and endocrinological problems raised by the evolution of viviparity in vertebrates. Symp Soc Exp Biol 1953;7:320-8.

2. Valencia-Ortega J, Saucedo R, Peña-Cano MI, Hernández-Valencia M, Cruz-Durán JG. Immune tolerance at the maternal-placental interface in healthy pregnancy and pre-eclampsia. J Obstet Gynaecol Res 2020;46:1067-76.
crossref pdf
3. Hunt JS. Stranger in a strange land. Immunol Rev 2006;213:36-47.
crossref pmid pmc
4. Huppertz B, Ghosh D, Sengupta J. An integrative view on the physiology of human early placental villi. Prog Biophys Mol Biol 2014;114:33-48.
crossref pmid
5. Li Z, Kurosawa O, Iwata H. Establishment of human trophoblast stem cells from human induced pluripotent stem cell-derived cystic cells under micromesh culture. Stem Cell Res Ther 2019;10:245.
crossref pmid pmc pdf
6. Tarrade A, Lai Kuen R, Malassiné A, Tricottet V, Blain P, Vidaud M,  et al. Characterization of human villous and extravillous trophoblasts isolated from first trimester placenta. Lab Invest 2001;81:1199-211.
crossref pmid pdf
7. Reyes L, Wolfe B, Golos T. Hofbauer cells: placental macrophages of fetal origin. Results Probl Cell Differ 2017;62:45-60.
crossref pmid
8. Rajagopalan S, Long EO. KIR2DL4 (CD158d): an activation receptor for HLA-G. Front Immunol 2012;3:258.
crossref pmid pmc
9. Rajagopalan S, Bryceson YT, Kuppusamy SP, Geraghty DE, van der Meer A, Joosten I, et al. Activation of NK cells by an endocytosed receptor for soluble HLA-G. PLoS Biol 2006;4:e9.
crossref pmid
10. Ishitani A, Sageshima N, Lee N, Dorofeeva N, Hatake K, Marquardt H, et al. Protein expression and peptide binding suggest unique and interacting functional roles for HLA-E, F, and G in maternal-placental immune recognition. J Immunol 2003;171:1376-84.
crossref pmid pdf
11. Hunt JS, Petroff MG, McIntire RH, Ober C. HLA-G and immune tolerance in pregnancy. FASEB J 2005;19:681-93.
crossref pmid pdf
12. Gustafsson C, Mjösberg J, Matussek A, Geffers R, Matthiesen L, Berg G,  et al. Gene expression profiling of human decidual macrophages: evidence for immunosuppressive phenotype. PLoS One 2008;3:e2078.
crossref pmid pmc
13. Gardner L, Moffett A. Dendritic cells in the human decidua. Biol Reprod 2003;69:1438-46.
crossref pmid
14. Xu X, Zhou Y, Wei H. Roles of HLA-G in the maternalfetal immune microenvironment. Front Immunol 2020;11:592010.
crossref pmid pmc
15. Rolle L, Memarzadeh Tehran M, Morell-García A, Raeva Y, Schumacher A, Hartig R,  et al. Cutting edge: IL-10-producing regulatory B cells in early human pregnancy. Am J Reprod Immunol 2013;70:448-53.
pmid
16. Hsu P, Santner-Nanan B, Dahlstrom JE, Fadia M, Chandra A, Peek M, et al. Altered decidual DC-SIGN+ antigenpresenting cells and impaired regulatory T-cell induction in preeclampsia. Am J Pathol 2012;181:2149-60.
crossref pmid
17. Sun F, Wang S, Du M. Functional regulation of decidual macrophages during pregnancy. J Reprod Immunol 2021;143:103264.
crossref pmid
18. Pantham P, Askelund KJ, Chamley LW. Trophoblast deportation part II: a review of the maternal consequences of trophoblast deportation. Placenta 2011;32:724-31.
crossref pmid
19. Khan S, Katabuchi H, Araki M, Nishimura R, Okamura H. Human villous macrophage-conditioned media enhance human trophoblast growth and differentiation in vitro. Biol Reprod 2000;62:1075-83.
crossref pmid
20. Nobs SP, Kopf M. Tissue-resident macrophages: guardians of organ homeostasis. Trends Immunol 2021;42:495-507.
crossref pmid
21. Strizova Z, Benesova I, Bartolini R, Novysedlak R, Cecrdlova E, Foley LK, et al. M1/M2 macrophages and their overlaps - myth or reality? Clin Sci (Lond) 2023;137:1067-93.
crossref pmid pmc pdf
22. Nadeau-Vallée M, Obari D, Palacios J, Brien MÈ, Duval C, Chemtob S, et al. Sterile inflammation and pregnancy complications: a review. Reproduction 2016;152:R277-92.
crossref pmid
23. Trowsdale J, Betz AG. Mother’s little helpers: mechanisms of maternal-fetal tolerance. Nat Immunol 2006;7:241-6.
crossref pmid pdf
24. Zulu MZ, Martinez FO, Gordon S, Gray CM. The elusive role of placental macrophages: the Hofbauer cell. J Innate Immun 2019;11:447-56.
crossref pmid pmc pdf
25. Bernischke K, Kaufmann P, Baergen R. Pathology of the human placenta. 5th ed. New York (NY): Springer; 2006.

26. Tang Z, Buhimschi IA, Buhimschi CS, Tadesse S, Norwitz E, Niven-Fairchild T, et al. Decreased levels of folate receptor-β and reduced numbers of fetal macrophages (Hofbauer cells) in placentas from pregnancies with severe pre-eclampsia. Am J Reprod Immunol 2013;70:104-15.
pmid pmc
27. Murray PJ. Macrophage polarization. Annu Rev Physiol 2017;79:541-66.
crossref pmid
28. Porta C, Riboldi E, Ippolito A, Sica A. Molecular and epigenetic basis of macrophage polarized activation. Semin Immunol 2015;27:237-48.
crossref pmid
29. Yao Y, Xu XH, Jin L. Macrophage polarization in physiological and pathological pregnancy. Front Immunol 2019;10:792.
crossref pmid pmc
30. Reyes L, Golos TG. Hofbauer cells: their role in healthy and complicated pregnancy. Front Immunol 2018;9:2628.
crossref pmid pmc
31. Martinez FO, Sica A, Mantovani A, Locati M. Macrophage activation and polarization. Front Biosci 2008;13:453-61.
crossref pmid
32. Sironi M, Martinez FO, D’Ambrosio D, Gattorno M, Polentarutti N, Locati M, et al. Differential regulation of chemokine production by Fcgamma receptor engagement in human monocytes: association of CCL1 with a distinct form of M2 monocyte activation (M2b, Type 2). J Leukoc Biol 2006;80:342-9.
pmid
33. Wang LX, Zhang SX, Wu HJ, Rong XL, Guo J. M2b macrophage polarization and its roles in diseases. J Leukoc Biol 2019;106:345-58.
crossref pmid pdf
34. Loegl J, Hiden U, Nussbaumer E, Schliefsteiner C, Cvitic S, Lang I, et al. Hofbauer cells of M2a, M2b and M2c polarization may regulate feto-placental angiogenesis. Reproduction 2016;152:447-55.
crossref pmid
35. Schliefsteiner C, Peinhaupt M, Kopp S, Lögl J, Lang-Olip I, Hiden U, et al. Human placental Hofbauer cells maintain an anti-inflammatory M2 phenotype despite the presence of gestational diabetes mellitus. Front Immunol 2017;8:888.
crossref pmid pmc
36. Mercnik MH, Schliefsteiner C, Fluhr H, Wadsack C. Placental macrophages present distinct polarization pattern and effector functions depending on clinical onset of preeclampsia. Front Immunol 2023;13:1095879.
crossref pmid pmc
37. Clark DE, Smith SK, Sharkey AM, Charnock-Jones DS. Localization of VEGF and expression of its receptors flt and KDR in human placenta throughout pregnancy. Hum Reprod 1996;11:1090-8.
pmid
38. Demir R, Kayisli UA, Seval Y, Celik-Ozenci C, Korgun ET, Demir-Weusten AY, et al. Sequential expression of VEGF and its receptors in human placental villi during very early pregnancy: differences between placental vasculogenesis and angiogenesis. Placenta 2004;25:560-72.
crossref pmid
39. Anteby EY, Natanson-Yaron S, Greenfield C, Goldman-Wohl D, Haimov-Kochman R, Holzer H, et al. Human placental Hofbauer cells express sprouty proteins: a possible modulating mechanism of villous branching. Placenta 2005;26:476-83.
crossref pmid
40. Chase V, Guller S. Hofbauer cells and placental viral infection. Reproductive Immunology 2021;295-309.
crossref
41. Schliefsteiner C, Ibesich S, Wadsack C. Placental Hofbauer cell polarization resists inflammatory cues in vitro. Int J Mol Sci 2020;21:736.
crossref pmid pmc
42. Pantazi P, Kaforou M, Tang Z, Abrahams VM, McArdle A, Guller S, et al. Placental macrophage responses to viral and bacterial ligands and the influence of fetal sex. iScience 2022;25:105653.
crossref pmid pmc
43. Schwartz DA, Baldewijns M, Benachi A, Bugatti M, Bulfamante G, Cheng K, et al. Hofbauer cells and COVID-19 in pregnancy. Arch Pathol Lab Med 2021;145:1328-40.
crossref pmid pdf
44. Romero R, Dey SK, Fisher SJ. Preterm labor: one syndrome, many causes. Science 2014;345:760-5.
crossref pmid pmc
45. Venkatesh KK, Jackson W, Hughes BL, Laughon MM, Thorp JM, Stamilio DM. Association of chorioamnionitis and its duration with neonatal morbidity and mortality. J Perinatol 2019;39:673-82.
crossref pmid pdf
46. Megli CJ, Coyne CB. Infections at the maternal-fetal interface: an overview of pathogenesis and defence. Nat Rev Microbiol 2022;20:67-82.
crossref pmid pdf
47. Fakonti G, Pantazi P, Bokun V, Holder B. Placental macrophage (Hofbauer cell) responses to infection during pregnancy: a systematic scoping review. Front Immunol 2022;12:756035.
crossref pmid pmc
48. Ben Amara A, Gorvel L, Baulan K, Derain-Court J, Buffat C, Vérollet C, et al. Placental macrophages are impaired in chorioamnionitis, an infectious pathology of the placenta. J Immunol 2013;191:5501-14.
crossref pmid pdf
49. Joerink M, Rindsjö E, van Riel B, Alm J, Papadogiannakis N. Placental macrophage (Hofbauer cell) polarization is independent of maternal allergen-sensitization and presence of chorioamnionitis. Placenta 2011;32:380-5.
crossref pmid
50. Hung TH, Chen SF, Hsu JJ, Hsieh CC, Hsueh S, Hsieh TT. Tumour necrosis factor-alpha converting enzyme in human gestational tissues from pregnancies complicated by chorioamnionitis. Placenta 2006;27:996-1006.
crossref pmid
51. Vinnars MT, Rindsjö E, Ghazi S, Sundberg A, Papadogiannakis N. The number of CD68(+) (Hofbauer) cells is decreased in placentas with chorioamnionitis and with advancing gestational age. Pediatr Dev Pathol 2010;13:300-4.
crossref pmid pdf
52. Toti P, Arcuri F, Tang Z, Schatz F, Zambrano E, Mor G, et al. Focal increases of fetal macrophages in placentas from pregnancies with histological chorioamnionitis: potential role of fibroblast monocyte chemotactic protein-1. Am J Reprod Immunol 2011;65:470-9.
crossref pmid
53. Semmes EC, Coyne CB. Innate immune defenses at the maternal-fetal interface. Curr Opin Immunol 2022;74:60-7.
crossref pmid
54. Plows JF, Stanley JL, Baker PN, Reynolds CM, Vickers MH. The pathophysiology of gestational diabetes mellitus. Int J Mol Sci 2018;19:3342.
crossref pmid pmc
55. Ning J, Zhang M, Cui D, Yang H. The pathologic changes of human placental macrophages in women with hyperglycemia in pregnancy. Placenta 2022;130:60-6.
crossref pmid
56. Sisino G, Bouckenooghe T, Aurientis S, Fontaine P, Storme L, Vambergue A. Diabetes during pregnancy influences Hofbauer cells, a subtype of placental macrophages, to acquire a pro-inflammatory phenotype. Biochim Biophys Acta 2013;1832:1959-68.
crossref pmid
57. Zhang M, Cui D, Yang H. The distributional characteristics of M2 macrophages in the placental chorionic villi are altered among the term pregnant women with uncontrolled type 2 diabetes mellitus. Front Immunol 2022;13:837391.
crossref pmid pmc
58. Gestational hypertension and preeclampsia: ACOG practice bulletin, number 222. Obstet Gynecol 2020;135:e237-60.
pmid
59. Ahn TG, Hwang JY. Preeclampsia and aspirin. Obstet Gynecol Sci 2023;66:120-32.
crossref pmid pmc pdf
60. Yang SW, Cho EH, Choi SY, Lee YK, Park JH, Kim MK, et al. DC-SIGN expression in Hofbauer cells may play an important role in immune tolerance in fetal chorionic villi during the development of preeclampsia. J Reprod Immunol 2017;124:30-7.
crossref
61. Gomez Perdiguero E, Klapproth K, Schulz C, Busch K, Azzoni E, Crozet L, et al. Tissue-resident macrophages originate from yolk-sac-derived erythro-myeloid progenitors. Nature 2015;518:547-51.
crossref pmid pdf
62. Stremmel C, Schuchert R, Wagner F, Thaler R, Weinberger T, Pick R, et al. Yolk sac macrophage progenitors traffic to the embryo during defined stages of development. Nat Commun 2018;9:75.
crossref pmid pmc pdf
63. Batorsky R, Ceasrine AM, Shook LL, Kislal S, Bordt EA, Devlin BA, et al. Hofbauer cells and fetal brain microglia share transcriptional profiles and responses to maternal diet-induced obesity. Cell Rep 2024;43:114326.
crossref pmid
64. Fitzgerald E, Shen M, Yong HEJ, Wang Z, Pokhvisneva I, Patel S, et al. Hofbauer cell function in the term placenta associates with adult cardiovascular and depressive outcomes. Nat Commun 2023;14:7120.
crossref pmid pmc pdf
65. Nimmerjahn F, Vidarsson G, Cragg MS. Effect of posttranslational modifications and subclass on IgG activity: from immunity to immunotherapy. Nat Immunol 2023;24:1244-55.
crossref pmid pdf
66. Choi H, Yang SW, Joo JS, Park M, Jin Y, Kim JW, et al. Sialylated IVIg binding to DC-SIGN +  Hofbauer cells induces immune tolerance through the caveolin-1/NF-kB pathway and IL-10 secretion. Clin Immunol 2023;246:109215.
crossref pmid


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