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Baby's First Macrophage: Temporal Regulation of Hofbauer Cell Phenotype Influences Ligand-Mediated Innate Immune Responses across Gestation.

ABSTRACT: The importance of fetal placental macrophages (Hofbauer cell [HCs]) is underscored by their appearance 18 d postconception and maintenance through term; however, how human HCs evolve during healthy pregnancy and how microenvironment and ontogeny impact phenotype and function remain unknown. In this study, we comprehensively classify human HCs ex vivo, interrogate phenotypic plasticity, and characterize antiviral immune responses through gestation. Activated HCs were abundant in early pregnancy and decreased by term; molecular signatures emphasize inflammatory phenotypes early in gestation. Frequency of HCs with regulatory phenotypes remained high through term. Furthermore, term HCs exhibited blunted responses to stimulation, indicating reduced plasticity. IFN-λ1 is a key placental IFN that appeared less protective than IFN-α, suggesting a potential weakness in antiviral immunity. Ligand-specific responses were temporally regulated: we noted an absence of inflammatory mediators and reduced antiviral gene transcription following RIG-I activation at term despite all HCs producing inflammatory mediators following IFN-γ plus LPS stimulation. Collectively, we demonstrate sequential, evolving immunity as part of the natural history of HCs through gestation.

SUBMITTER: Swieboda D

PROVIDER: S-EPMC7870092 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundCongenital infection of the fetus via trans-placental passage of pathogens can result in severe morbidity and mortality. Even without transmission to the fetus, infection of the placenta itself is associated with pregnancy complications including pregnancy loss and preterm birth. Placental macrophages, also termed Hofbauer cells (HBCs), are fetal-origin macrophages residing in the placenta that are likely involved in responding to placental infection and protection of the developing fetus. As HBCs are the only immune cell present in the villous placenta, they represent one of the final opportunities for control of infection and prevention of passage to the developing fetus.Objective and rationaleThe objective of this review was to provide a systematic overview of the literature regarding HBC responses during infection in pregnancy, including responses to viral, bacterial, and parasitic pathogens.MethodsPubMed and Scopus were searched on May 20th, 2021, with no limit on publication date, to identify all papers that have studied placental macrophages/Hofbauer cells in the context of infection. The following search strategy was utilized: (hofbauer* OR "hofbauer cells" OR "hofbauer cell" OR "placental macrophage" OR "placental macrophages") AND [infect* OR virus OR viral OR bacteri* OR parasite* OR pathogen* OR LPS OR "poly(i:c)" OR toxoplasm* OR microb* OR HIV)].Outcomes86 studies were identified for review. This included those that investigated HBCs in placentas from pregnancies complicated by maternal infection and in vitro studies investigating HBC responses to pathogens or Pathogen-Associated Molecular Patterns (PAMPs). HBCs can be infected by a variety of pathogens, and HBC hyperplasia was a common observation. HBCs respond to pathogen infection and PAMPs by altering their transcriptional, translational and secretion profiles. Co-culture investigations demonstrate that they can replicate and transmit pathogens to other cells. In other cases, they may eliminate the pathogen through a variety of mechanisms including phagocytosis, cytokine-mediated pathogen elimination, release of macrophage extracellular traps and HBC-antibody-mediated neutralization. HBC responses differ across gestation and may be influenced by pre-existing immunity. Clinical information, including gestational age at infection, gestational age of the samples, mode of sample collection and pregnancy outcome were missing for the majority of studies.

Project description:The nature of the culture dish surface and the technique used to detach adherent cells could very likely influence the cell viability and cell membrane protein integrity of harvested macrophages. Several previous studies assessed the detachment efficacies of enzymatic and non-enzymatic methods for harvesting the single cell suspensions of macrophages, but a comprehensive study assessing different dissociation methods and culture conditions for detaching functionally different macrophage populations has not yet been reported. In this study, via the well-established GM-CSF and M-CSF differentiated bone marrow derived macrophage models (GM-BMDMs and M-BMDMs), we compared four commonly used enzymatic (trypsin and accutase) and non-enzymatic (PBS and EDTA) dissociation methods along with necessary mechanical detaching steps (scraping and pipetting) to evaluate the viable cell recovery and cell surface marker integrality of GM-BMDMs and M-BMDMs cultured on standard cell culture dish (TC dish), or on culture dish (noTC dish) that was not conditioned to enhance adherence. The data showed that accutase yielded a better recovery of viable cells comparing with PBS and EDTA, especially for tightly adherent GM-BMDMs on TC dishes, with a relatively higher level of detected cell membrane marker F4/80 than trypsin. An additional gradient centrifugation-based dead cell removal approach could increase the proportion of viable cells for TC cultured GM-BMDMs after accutase dissociation. Furthermore, transcriptome analysis was performed to evaluate the putative influence of culture dishes. At steady state, BMDMs cultured on noTC dishes exhibited more proinflammatory gene expression signatures (e.g. IL6, CXCL2 and ILlβ) and functions (e.g. TNF and IL17 signaling pathways). Similar inflammatory responses were observed upon LPS challenge regardless of culture conditions and differentiation factors. However, in LPS treated samples, the difference of gene expression patterns, signaling pathways and molecular functions between TC and noTC cultured BMDMs were largely dependent on the types of growth factors (M-CSF and GM-CSF). This observation might provide valuable information for in vitro macrophage studies.

Project description:BackgroundMonocytes and macrophages contribute to the dysfunction of immune responses in human filariasis. During patent infection monocytes encounter microfilariae in the blood, an event that occurs in asymptomatically infected filariasis patients that are immunologically hyporeactive.AimTo determine whether blood microfilariae directly act on blood monocytes and in vitro generated macrophages to induce a regulatory phenotype that interferes with innate and adaptive responses.Methodology and principal findingsMonocytes and in vitro generated macrophages from filaria non-endemic normal donors were stimulated in vitro with Brugia malayi microfilarial (Mf) lysate. We could show that monocytes stimulated with Mf lysate develop a defined regulatory phenotype, characterised by expression of the immunoregulatory markers IL-10 and PD-L1. Significantly, this regulatory phenotype was recapitulated in monocytes from Wuchereria bancrofti asymptomatically infected patients but not patients with pathology or endemic normals. Monocytes from non-endemic donors stimulated with Mf lysate directly inhibited CD4+ T cell proliferation and cytokine production (IFN-?, IL-13 and IL-10). IFN-? responses were restored by neutralising IL-10 or PD-1. Furthermore, macrophages stimulated with Mf lysate expressed high levels of IL-10 and had suppressed phagocytic abilities. Finally Mf lysate applied during the differentiation of macrophages in vitro interfered with macrophage abilities to respond to subsequent LPS stimulation in a selective manner.Conclusions and significanceConclusively, our study demonstrates that Mf lysate stimulation of monocytes from healthy donors in vitro induces a regulatory phenotype, characterized by expression of PD-L1 and IL-10. This phenotype is directly reflected in monocytes from filarial patients with asymptomatic infection but not patients with pathology or endemic normals. We suggest that suppression of T cell functions typically seen in lymphatic filariasis is caused by microfilaria-modulated monocytes in an IL-10-dependent manner. Together with suppression of macrophage innate responses, this may contribute to the overall down-regulation of immune responses observed in asymptomatically infected patients.

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Baby's First Macrophage: Temporal Regulation of Hofbauer Cell Phenotype Influences Ligand-Mediated Innate Immune Responses across Gestation.

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