Human Chorionic Gonadotropin Induces Human Macrophages to Form Intracytoplasmic Vacuoles Mimicking Hofbauer Cells in Human Chorionic Villi

Abstract

The most characteristic morphological feature of macrophages in the stroma of placental villi, known as Hofbauer cells, is their highly vacuolated appearance. They also show positive immunostaining for human chorionic gonadotropin (hCG) and express messenger ribonucleic acid of the luteinizing hormone/chorionic gonadotropin receptor with a deletion of exon 9 (LH/CG-R Δ9). Maternal hCG enters fetal plasma through the mesenchyme of the placental villi and promotes male sexual differentiation in early pregnancy; therefore, excess hCG may induce aberrant genital differentiation and hCG must be adjusted at the fetomaternal interface. We hypothesized that hCG is regulated by Hofbauer cells and that their peculiar vacuoles are involved in a cell-specific function. To assess the morphological modification and expression of LH/CG-R Δ9 in human macrophages after hCG exposure, the present study examined phorbol 12-myristate 13-acetate (PMA)-treated THP-1 cells, a human monocyte-macrophage cell line. hCG induced transient vacuole formation in PMA-treated THP-1 cells, morphologically mimicking Hofbauer cells. Immunocytochemistry showed that PMA-treated THP-1 cells incorporated hCG but not luteinizing hormone or follicle-stimulating hormone. Western blotting analyses demonstrated that PMA-treated THP-1 cells expressed an immunoreactive 60-kDa protein, designated as endogenous LH/CG-R Δ9. hCG induced a transient reduction in the LH/CG-R Δ9, which was synchronous with the appearance of cytoplasmic vacuoles. In conclusion, human macrophages regulating hCG via cytoplasmic LH/CG-R Δ9 mimic the morphological characteristics of Hofbauer cells. Their vacuoles may be associated with their cell-specific function to protect the fetus from exposure to excess maternal hCG during pregnancy.

Human chorionic gonadotropin and risk of pre‐eclampsia: prospective population‐based cohort study

“…In general, hCG has a protective effect on pregnancy and promotes fetal survival by promoting immune tolerance via interaction with macrophages, natural killer cells, and B‐ and T‐lymphocytes. However, in higher doses, hCG may exhibit harmful effects on fetal development and may induce an immune cell response with altered cytokine and reactive oxygen species production, triggering exaggerated sFlt‐1 production and thereby reinforcing the cumulative effect of factors predisposing women to pre‐eclampsia. Alternatively, higher availability of sFlt‐1 and anti‐angiogenic effects characterizing pre‐eclampsia might be due to hCG‐stimulated binding of PlGF to membrane and local circulating receptors.…”

Endocrine Factors Modulating Immune Responses in Pregnancy

“…More precisely, Katabuchi and colleagues recently demonstrated that hCG induces transient vacuole formation in human monocytes, morphologically mimicking Hofbauer cells. The authors suggest that Hofbauer cells and especially their vacuoles are involved in the protection of fetal tissue from high amounts of maternal hCG (49). Besides an effect of steroid hormones and gonadotropins on monocytes and macrophages, AFP is suggested to have an influence on both innate immune cell types.…”

Human Placental Hofbauer Cells Maintain an Anti-inflammatory M2 Phenotype despite the Presence of Gestational Diabetes Mellitus

“…They possess a very specific morphology characterized by an occurrence of visible granulose vacuoles. A recent study showed that these vacuoles are a result of exposure to and uptake of β-hCG and that this specific phenotype can also be promoted in other macrophage cell lines by stimulation with β-hCG (18). We and others have shown that HBCs have an M2 anti-inflammatory, regulatory phenotype.…”