RESUMO
Women with antiphospholipid syndrome (APS) are at high risk for miscarriage and preeclampsia. Unlike pro-thrombotic systemic APS, obstetric APS is associated with insufficient placentation, as well as inflammation and vascular dysfunction at the maternal-fetal interface. Antiphospholipid antibodies (aPL) can target the placental trophoblast and induce inflammation. We reported that aPL trigger trophoblast cells to produce elevated levels of IL-8 through activation of Toll-like receptor 4 (TLR4). Downstream of TLR4, we found this IL-8 response is mediated by a TLR8-activating microRNA (miR), miR-146a-3p, which is also released by the trophoblast via extracellular vesicles (EVs). Since endothelial dysfunction is a feature of obstetric APS, we sought to determine if other miRs that can activate the RNA sensors, TLR7 and/or TLR8, are released by the trophoblast via EVs after exposure to aPL, and if these EVs can activate human endometrial endothelial cells (HEECs). Using a human first trimester extravillous trophoblast cell line we found that aPL elevated their release of small EVs (<150â¯nm). These extracellular vesicles released from trophoblast cells exposed to aPL expressed elevated levels of TLR7/8-activating miR-21a and miR-29a, in addition to the previously reported miR-146a-3p. Extracellular vesicles from aPL-exposed human trophoblast cells triggered human endometrial endothelial cells to generate an inflammatory IL-8 response, in part through TLR7. This study highlights EVs as a mode of communication between the placenta and the maternal vasculature, as well as a potential role for TLR7/8-activating miRs in contributing to inflammation at the maternal-fetal interface in obstetric APS.
Assuntos
Anticorpos Antifosfolipídeos , Síndrome Antifosfolipídica , Vesículas Extracelulares , MicroRNAs , Receptor 7 Toll-Like , Receptor 8 Toll-Like , Trofoblastos , Humanos , Feminino , Trofoblastos/metabolismo , Trofoblastos/imunologia , MicroRNAs/metabolismo , MicroRNAs/genética , Receptor 7 Toll-Like/metabolismo , Vesículas Extracelulares/metabolismo , Vesículas Extracelulares/imunologia , Gravidez , Receptor 8 Toll-Like/metabolismo , Receptor 8 Toll-Like/imunologia , Síndrome Antifosfolipídica/imunologia , Síndrome Antifosfolipídica/metabolismo , Anticorpos Antifosfolipídeos/imunologia , Anticorpos Antifosfolipídeos/metabolismo , Endométrio/metabolismo , Endométrio/imunologia , Endométrio/patologia , Células Endoteliais/metabolismo , Células Endoteliais/imunologia , Linhagem Celular , Interleucina-8/metabolismoRESUMO
Implantation and maintenance of pregnancy involve intricate immunological processes that enable the developing fetus to coexist with the maternal immune system. Progesterone, a critical hormone during pregnancy, is known to promote immune tolerance and prevent preterm labor. However, the mechanism by which progesterone mediates these effects remains unclear. In this study, we investigated the role of the non-classical progesterone receptor membrane component 1 (PGRMC1) in progesterone signaling at the maternal-fetal interface. Using JEG3 cells, a trophoblast model cell line, we observed that progesterone stimulation increased the expression of human leukocyte antigen-C (HLA-C) and HLA-G, key molecules involved in immune tolerance. We also found that progesterone upregulated the expression of the transcription factor ELF3, which is known to regulate trophoblast-specific HLA-C expression. Interestingly, JEG3 cells lacked expression of classical progesterone receptors (PRs) but exhibited high expression of PGRMC1, a finding we confirmed in primary trophoblasts by mining sc-RNA seq data from human placenta. To investigate the role of PGRMC1 in progesterone signaling, we used CRISPR/Cas9 technology to knockout PGRMC1 in JEG3 cells. PGRMC1-deficient cells showed a diminished response to progesterone stimulation. Furthermore, we found that the progesterone antagonist RU486 inhibited ELF3 expression in a PGRMC1-dependent manner, suggesting that RU486 acts as a progesterone antagonist by competing for receptor binding. Additionally, we found that RU486 inhibited cell invasion, an important process for successful pregnancy, and this inhibitory effect was dependent on PGRMC1. Our findings highlight the crucial role of PGRMC1 in mediating the immunoregulatory effects of progesterone at the maternal-fetal interface.
Assuntos
Proteínas de Membrana , Progesterona , Receptores de Progesterona , Trofoblastos , Humanos , Receptores de Progesterona/metabolismo , Feminino , Gravidez , Progesterona/metabolismo , Progesterona/farmacologia , Proteínas de Membrana/metabolismo , Proteínas de Membrana/genética , Trofoblastos/metabolismo , Trofoblastos/imunologia , Placenta/imunologia , Placenta/metabolismo , Transdução de Sinais/imunologia , Troca Materno-Fetal/imunologia , Implantação do Embrião/imunologiaRESUMO
The immune tolerance microenvironment is crucial for the establishment and maintenance of pregnancy at the maternal-fetal interface. The maternal-fetal interface is a complex system containing various cells, including lymphocytes, decidual stromal cells, and trophoblasts. Macrophages are the second-largest leukocytes at the maternal-fetal interface, which has been demonstrated to play essential roles in remodeling spiral arteries, maintaining maternal-fetal immune tolerance, and regulating trophoblast's biological behaviors. Many researchers, including us, have conducted a series of studies on the crosstalk between macrophages and trophoblasts at the maternal-fetal interface: on the one hand, macrophages can affect the invasion and migration of trophoblasts; on the other hand, trophoblasts can regulate macrophage polarization and influence the state of the maternal-fetal immune microenvironment. In this review, we systemically introduce the functions of macrophages and trophoblasts and the cell-cell interaction between them for the establishment and maintenance of pregnancy. Advances in this area will further accelerate the basic research and clinical translation of reproductive medicine.
Assuntos
Feto/imunologia , Tolerância Imunológica/imunologia , Macrófagos/fisiologia , Gravidez/imunologia , Trofoblastos/fisiologia , Animais , Comunicação Celular , Movimento Celular , Microambiente Celular , Citocinas/fisiologia , Vesículas Extracelulares/fisiologia , Feminino , Humanos , Ativação de Macrófagos , Macrófagos/classificação , Macrófagos/citologia , Macrófagos/imunologia , Camundongos , Trofoblastos/classificação , Trofoblastos/citologia , Trofoblastos/imunologiaRESUMO
Successful implantation requires the coordinated migration and invasion of trophoblast cells from out of the blastocyst and into the endometrium. This process relies on signals produced by cells in the maternal endometrium. However, the relative contribution of stroma cells remains unclear. The study of human implantation has major technical limitations, therefore the need of in vitro models to elucidate the molecular mechanisms. Using a recently described 3D in vitro models we evaluated the interaction between trophoblasts and human endometrial stroma cells (hESC), we assessed the process of trophoblast migration and invasion in the presence of stroma derived factors. We demonstrate that hESC promotes trophoblast invasion through the generation of an inflammatory environment modulated by TNF-α. We also show the role of stromal derived IL-17 as a promoter of trophoblast migration through the induction of essential genes that confer invasive capacity to cells of the trophectoderm. In conclusion, we describe the characterization of a cellular inflammatory network that may be important for blastocyst implantation. Our findings provide a new insight into the complexity of the implantation process and reveal the importance of inflammation for embryo implantation.
Assuntos
Movimento Celular , Implantação do Embrião , Endométrio/efeitos dos fármacos , Interleucina-17/metabolismo , Comunicação Parácrina/efeitos dos fármacos , Células Estromais/efeitos dos fármacos , Trofoblastos/metabolismo , Fator de Necrose Tumoral alfa/farmacologia , Adesão Celular , Diferenciação Celular , Linhagem Celular , Endométrio/imunologia , Endométrio/metabolismo , Feminino , Humanos , Interleucina-17/genética , Receptores Tipo I de Fatores de Necrose Tumoral/agonistas , Receptores Tipo I de Fatores de Necrose Tumoral/genética , Receptores Tipo I de Fatores de Necrose Tumoral/metabolismo , Via Secretória , Transdução de Sinais , Células Estromais/imunologia , Células Estromais/metabolismo , Trofoblastos/imunologiaRESUMO
The syncytiotrophoblast (STB) of human placenta constitutively and throughout pregnancy produces and secretes exosomes - nanometer-sized membrane-bound extracellular vesicles from the endosomal compartment that convey cell-cell contact 'by proxy' transporting information between donor and recipient cells locally and at a distance. Released in the maternal blood, STB-derived exosomes build an exosomal gradient around the feto-placental unit acting as a shield that protects the fetus from maternal immune attack. They carry signal molecules and ligands that comprise distinct immunosuppressive protein signatures which interfere with maternal immune mechanisms, potentially dangerous for the ongoing pregnancy. We discuss three immunosuppressive signatures carried by STB exosomes and their role in three important immune mechanisms 1) NKG2D receptor-mediated cytotoxicity, 2) apoptosis of activated immune cells and 3) PD-1-mediated immunosuppression and priming of T regulatory cells. A schematic presentation is given on how these immunosuppressive protein signatures, delivered by STB exosomes, modulate the maternal immune system and contribute to the development of maternal-fetal tolerance.
Assuntos
Biomarcadores , Exossomos/metabolismo , Imunomodulação , Trofoblastos/imunologia , Trofoblastos/metabolismo , Apoptose/imunologia , Endossomos/imunologia , Endossomos/metabolismo , Exossomos/imunologia , Proteína Ligante Fas/metabolismo , Feminino , Humanos , Proteínas de Checkpoint Imunológico/genética , Proteínas de Checkpoint Imunológico/metabolismo , Tolerância Imunológica , Ligantes , Troca Materno-Fetal/imunologia , Subfamília K de Receptores Semelhantes a Lectina de Células NK/metabolismo , Gravidez , Proteoma , Proteômica/métodosRESUMO
Human Leukocyte Antigen-G (HLA-G) prevents the activity of immune cells and is decreased in women with preeclampsia. We aimed to investigate the associations between circulating soluble HLA-G (sHLA-G) and 92 cardiovascular disease-related biomarkers from a previously published multiplex study in women with preeclampsia and controls. We found 15 markers significantly associated with circulating sHLA-G in univariate analyses. After multivariable adjusted regression, only proto-oncogene tyrosine-protein kinase Src (SRC) and vascular endothelial growth factor D were significantly associated with sHLA-G. Low SRC, previously observed in the circulation of preeclamptic women, may be regulated by low sHLA-G, and reflect decreased trophoblast differentiation and syncytical formation.
Assuntos
Antígenos HLA-G/sangue , Pré-Eclâmpsia/epidemiologia , Trofoblastos/imunologia , Biomarcadores/sangue , Estudos de Casos e Controles , Diferenciação Celular/imunologia , Cesárea , Feminino , Antígenos HLA-G/imunologia , Fatores de Risco de Doenças Cardíacas , Humanos , Pré-Eclâmpsia/sangue , Pré-Eclâmpsia/diagnóstico , Pré-Eclâmpsia/imunologia , Gravidez , Medição de Risco/métodos , Fator D de Crescimento do Endotélio Vascular/sangue , Quinases da Família src/sangueRESUMO
The success of pregnancy relies on the fine adjustment of the maternal immune system to tolerate the allogeneic fetus. Trophoblasts carrying paternal antigens are the only fetal-derived cells that come into direct contact with the maternal immune cells at the maternal-fetal interface. The crosstalk between trophoblasts and decidual immune cells (DICs) via cell-cell direct interaction and soluble factors such as chemokines and cytokines is a core event contributing to the unique immunotolerant microenvironment. Abnormal trophoblasts-DICs crosstalk can lead to dysregulated immune situations, which is well known to be a potential cause of a series of pregnancy complications including recurrent spontaneous abortion (RSA), which is the most common one. Immunotherapy has been applied to RSA. However, its development has been far less rapid or mature than that of cancer immunotherapy. Elucidating the mechanism of maternal-fetal immune tolerance, the theoretical basis for RSA immunotherapy, not only helps to understand the establishment and maintenance of normal pregnancy but also provides new therapeutic strategies and promotes the progress of immunotherapy against pregnancy-related diseases caused by disrupted immunotolerance. In this review, we focus on recent progress in the maternal-fetal immune tolerance mediated by trophoblasts-DICs crosstalk and clinical application of immunotherapy in RSA. Advancement in this area will further accelerate the basic research and clinical transformation of reproductive immunity and tumor immunity.
Assuntos
Decídua/imunologia , Privilégio Imunológico/imunologia , Trofoblastos/imunologia , Aborto Habitual/imunologia , Aborto Habitual/terapia , Animais , Feminino , Humanos , Imunoterapia/métodos , GravidezRESUMO
MiR-126-3p is a prototype of an endothelial miRNA and has protective effects on endothelial cells. However, little is known about the effects of miR-126-3p on placental trophoblasts. In the present study, we tested the hypothesis that aberrant miR-126-3p expression is present in preeclamptic placenta which contributes to increased inflammatory response in trophoblasts. Placentas were obtained immediately after delivery from normotensive and preeclamptic pregnancies. Villous tissue was either fixed with formalin or used for trophoblast isolation. Trophoblast miR-126-3p expression was assessed by in situ hybridization of formalin-fixed tissue sections and by RT-PCR in cultured syncytiotrophoblasts. Culture medium was collected for measurement of IL-6, TNFα, and 8-Isoprostane production by ELISA and total cellular protein was collected for evaluation of HIF1α expression by Western blot. Effects of overexpression of miR-126-3p in trophoblasts on cytokine production were tested by transfection of pre-mir-126, a precursor of miR-126, into primary isolated trophoblasts. We found that downregulation of miR-126-3p expression was associated with increased IL-6 and TNFα production in trophoblasts from preeclamptic placentas vs. normal placentas. Moreover, transient overexpression of miR-126-3p significantly reduced IL-6 and TNFα production in trophoblasts from both normal and preeclamptic placentas. We further found that increase in miR-126-3p expression not only suppressed hypoxia-induced increases in IL-6 and TNFα production, but also attenuated hypoxia-induced increases in HIF1α expression and 8-Isoprostane production in trophoblasts cultured under hypoxic condition. These results provide plausible evidence that downregulation of miR-126-3p expression reduces anti-inflammatory and anti-oxidative stress activities in placental trophoblasts in preeclampsia.
Assuntos
Regulação para Baixo/imunologia , MicroRNAs/metabolismo , Pré-Eclâmpsia/imunologia , Trofoblastos/patologia , Adulto , Hipóxia Celular/imunologia , Células Cultivadas , Dinoprosta/análogos & derivados , Dinoprosta/metabolismo , Feminino , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Interleucina-6/genética , MicroRNAs/genética , Estresse Oxidativo/genética , Estresse Oxidativo/imunologia , Pré-Eclâmpsia/patologia , Gravidez , Trofoblastos/imunologia , Trofoblastos/metabolismo , Fator de Necrose Tumoral alfa/genética , Adulto JovemRESUMO
HLA-C arose during evolution of pregnancy in the great apes 10 to 15 million years ago. It has a dual function on placental extravillous trophoblasts (EVTs) as it contributes to both tolerance and immunity at the maternal-fetal interface. The mode of its regulation is of considerable interest in connection with the biology of pregnancy and pregnancy abnormalities. First-trimester primary EVTs in which HLA-C is highly expressed, as well as JEG3, an EVT model cell line, were employed. Single-cell RNA-seq data and quantitative PCR identified high expression of the transcription factor ELF3 in those cells. Chromatin immunoprecipitation (ChIP)-PCR confirmed that both ELF3 and MED1 bound to the proximal HLA-C promoter region. However, binding of RFX5 to this region was absent or severely reduced, and the adjacent HLA-B locus remained closed. Expression of HLA-C was inhibited by ELF3 small interfering RNAs (siRNAs) and by wrenchnolol treatment. Wrenchnolol is a cell-permeable synthetic organic molecule that mimics ELF3 and is relatively specific for binding to ELF3's coactivator, MED23, as our data also showed in JEG3. Moreover, the ELF3 gene is regulated by a superenhancer that spans more than 5 Mb, identified by assay for transposase-accessible chromatin using sequencing (ATAC-seq), as well as by its sensitivity to (+)-JQ1 (inhibitor of BRD4). ELF3 bound to its own promoter, thus creating an autoregulatory feedback loop that establishes expression of ELF3 and HLA-C in trophoblasts. Wrenchnolol blocked binding of MED23 to ELF3, thus disrupting the positive-feedback loop that drives ELF3 expression, with down-regulation of HLA-C expression as a consequence.
Assuntos
Proteínas de Ligação a DNA/genética , Elementos Facilitadores Genéticos , Retroalimentação Fisiológica , Antígenos HLA-C/genética , Proteínas Proto-Oncogênicas c-ets/genética , Fatores de Transcrição/genética , Trofoblastos/imunologia , Aborto Legal , Adamantano/farmacologia , Azepinas/farmacologia , Linhagem Celular , Proteínas de Ligação a DNA/antagonistas & inibidores , Proteínas de Ligação a DNA/imunologia , Feminino , Regulação da Expressão Gênica no Desenvolvimento/imunologia , Antígenos HLA-B/genética , Antígenos HLA-B/imunologia , Antígenos HLA-C/imunologia , Humanos , Imunidade Materno-Adquirida , Indóis/farmacologia , Complexo Mediador/genética , Complexo Mediador/imunologia , Subunidade 1 do Complexo Mediador/genética , Subunidade 1 do Complexo Mediador/imunologia , Gravidez , Primeiro Trimestre da Gravidez , Cultura Primária de Células , Regiões Promotoras Genéticas , Ligação Proteica , Proteínas Proto-Oncogênicas c-ets/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-ets/imunologia , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/imunologia , Fatores de Transcrição de Fator Regulador X/genética , Fatores de Transcrição de Fator Regulador X/imunologia , Transdução de Sinais , Fatores de Transcrição/antagonistas & inibidores , Fatores de Transcrição/imunologia , Triazóis/farmacologia , Trofoblastos/citologia , Trofoblastos/efeitos dos fármacosRESUMO
Cells produce cytoplasmic vesicles to facilitate the processing and transport of RNAs, proteins, and other signaling molecules among intracellular organelles. Moreover, most cells release a range of extracellular vesicles (EVs) that mediate intercellular communication in both physiological and pathological settings. In addition to a better understanding of their biological functions, the diagnostic and therapeutic prospects of EVs, particularly the nano-sized small EVs (sEVs, exosomes), are currently being rigorously pursued. While EVs and viruses such as retroviruses might have evolved independently, they share a number of similar characteristics, including biogenesis pathways, size distribution, cargo, and cell-targeting mechanisms. The interplay of EVs with viruses has profound effects on viral replication and infectivity. Our research indicates that sEVs, produced by primary human trophoblasts, can endow other non-placental cell types with antiviral response. Better insights into the interaction of EVs with viruses may illuminate new ways to attenuate viral infections during pregnancy, and perhaps develop new antiviral therapeutics to protect the feto-placental unit during critical times of human development.
Assuntos
Vesículas Extracelulares/imunologia , Placenta/imunologia , Gravidez/imunologia , Infecções por Retroviridae/imunologia , Retroviridae/fisiologia , Trofoblastos/imunologia , Feminino , Humanos , Nanoestruturas , Especificidade de Órgãos , Virulência , Replicação ViralRESUMO
Macrophages are major components of decidual microenvironment that play an important role in human implantation and placentation. Trophoblasts which migrate into the endometrium and interplay with decidual cells, have been reported to participate in the polarization of macrophages. However, the potential mechanisms of trophoblasts modulating M2 macrophages polarization still need further exploration. Herein, we used the co-cultured model to investigate the interaction between macrophages and trophoblasts. Our results illustrated that when co-cultured with trophoblasts, macrophages tended to polarize to M2-subtype, accompanied by increased expression of multiple M2 markers including CD206 and CCL18 mRNA expression and IL-10 and TGF-ß protein level. Further experiments identified that trophoblast-derived IL-6, as the major contributor, promoted M2 macrophages polarization by activating Stat3 pathway. Moreover, activated M2 macrophages exerted a promoting role in the invasion and migration of trophoblasts in a feedback manner. Clinically, results from histology demonstrated that IL-6 expression in placental villous tissues was positive correlated with CD206-positive macrophage infiltration in decidua in normal pregnancy patients. Altogether, our findings indicate that trophoblasts induce M2 macrophages polarization via IL-6/Stat3 signal pathway, which in turn promote the invasion and migration of trophoblasts. These results provide insights into the crosstalk between macrophages and trophoblasts at maternal-fetal microenvironment in normal pregnancy.
Assuntos
Interleucina-6/metabolismo , Macrófagos/metabolismo , Comunicação Parácrina , Fator de Transcrição STAT3/metabolismo , Trofoblastos/metabolismo , Adulto , Técnicas de Cocultura , Retroalimentação Fisiológica , Feminino , Humanos , Interleucina-6/genética , Macrófagos/imunologia , Fenótipo , Gravidez , Transdução de Sinais , Células THP-1 , Trofoblastos/imunologiaRESUMO
Epitope H contains an O-linked N-acetylglucosamine (O-GlcNAcH) residue in a specific conformation and/or environment recognized by the mouse monoclonal antibody H. O-GlcNAcH is present in several types of cells and in several polypeptides, including cytokeratin 8 and vimentin, on the latter in cells under stress. In the present work, we examined the expression of the O-GlcNAcH in 60 cases of endometrial curettings from missed miscarriage cases containing normal and simple hydropic degenerated chorionic villi in each case, using monoclonal antibody H and indirect immunoperoxidase and Western blot immunoblot. In all cases examined the expression of the O-GlcNAcH was cytoplasmic as follows: (1) syncytiotrophoblastic cells showed very low expression in chorionic villi (CV) with nonhydropic degeneration (NHD) and high expression in hydropic degenerated (HD) CV; (2) cytotrophoblastic cells showed low expression in CV with NHD and high expression in HD CV; (3) fibroblastic cells showed high expression in CV with NHD and very low expression in HD CV; (4) histiocytes showed very low expression in both types of CV; (5) endothelial cells showed high expression in both types of CV. An immunoblot of CV from one case of a legal abortion from a normal first-trimester pregnancy showed 5 polypeptides with 118.5, 106.3, 85, 53, and 36.7 kD bearing the epitope H and the 53 kD corresponded to cytokeratin 8. The expression of the O-GlcNAcH is upregulated in the trophoblastic cells and downregulated in the fibroblastic cells in the HD CV in comparison to the NHD CV.
Assuntos
Aborto Espontâneo/metabolismo , Acetilglucosamina/metabolismo , Anticorpos Monoclonais/imunologia , Epitopos/imunologia , Epitopos/metabolismo , Queratina-8/metabolismo , Vimentina/metabolismo , Aborto Espontâneo/imunologia , Acetilglucosamina/imunologia , Vilosidades Coriônicas/imunologia , Vilosidades Coriônicas/metabolismo , Citoplasma/metabolismo , Regulação para Baixo , Células Endoteliais/imunologia , Células Endoteliais/metabolismo , Feminino , Fibroblastos/imunologia , Fibroblastos/metabolismo , Humanos , Gravidez , Primeiro Trimestre da Gravidez/imunologia , Primeiro Trimestre da Gravidez/metabolismo , Trofoblastos/imunologia , Trofoblastos/metabolismo , Regulação para CimaRESUMO
Zika virus (ZIKV) re-emerged after circulating almost undetected for many years and the last spread in 2015 was the major outbreak reported. ZIKV infection was associated with congenital fetal growth anomalies such as microcephaly, brain calcifications, and low birth weight related to fetal growth restriction. In this study, we investigated the effect of ZIKV infection on first trimester trophoblast cell function and metabolism. We also studied the interaction of trophoblast cells with decidual immune populations. Results presented here demonstrate that ZIKV infection triggered a strong antiviral response in first trimester cytotrophoblast-derived cells, impaired cell migration, increased glucose uptake and GLUT3 expression, and reduced brain derived neurotrophic factor (BDNF) expression. ZIKV infection also conditioned trophoblast cells to favor a tolerogenic response since an increased recruitment of CD14+ monocytes bearing an anti-inflammatory profile, increased CD4+ T cells and NK CD56Dim and NK CD56Bright populations and an increment in the population CD4+ FOXP3+ IL-10+ cells was observed. Interestingly, when ZIKV infection of trophoblast cells occurred in the presence of the vasoactive intestinal peptide (VIP) there was lower detection of viral RNA and reduced toll-like receptor-3 and viperin messenger RNA expression, along with reduced CD56Dim cells trafficking to trophoblast conditioned media. The effects of ZIKV infection on trophoblast cell function and immune-trophoblast interaction shown here could contribute to defective placentation and ZIKV persistence at the fetal-maternal interface. The inhibitory effect of VIP on ZIKV infection of trophoblast cells highlights its potential as a candidate molecule to interfere ZIKV infection during early pregnancy.
Assuntos
Placenta/virologia , Placentação/fisiologia , Trofoblastos/imunologia , Trofoblastos/virologia , Infecção por Zika virus/patologia , Fator Neurotrófico Derivado do Encéfalo/biossíntese , Linfócitos T CD4-Positivos/imunologia , Movimento Celular/fisiologia , Células Cultivadas , Anormalidades Congênitas/virologia , Metabolismo Energético/fisiologia , Feminino , Feto/anormalidades , Feto/virologia , Glucose/metabolismo , Transportador de Glucose Tipo 3/biossíntese , Humanos , Placenta/citologia , Gravidez , Primeiro Trimestre da Gravidez , Peptídeo Intestinal Vasoativo/metabolismo , Zika virus/imunologiaRESUMO
A successful pregnancy requires that the maternal immune system recognizes and tolerates the semi-allogeneic fetus without compromising the capability of protecting both mother and fetus from various pathogens. Decidual macrophages present unique phenotypes to play a key role in the establishment of the immunological aspects of maternal-fetal interaction. Dysfunction of decidual macrophages gives rise to pregnancy complications such as preeclampsia, recurrent spontaneous miscarriage, preterm labor and fetal growth restriction. Here, we reviewed the latest knowledge on the origin, differentiation, unique phenotype and function of macrophages in normal pregnancy and in pregnancy complications. We mainly focused on the significant roles of decidual macrophages in the process of extravillous trophoblast invasion, spiral arterial remodeling, decidual stromal cells cultivation and immune tolerance maintenance in normal pregnancy, and their pathological roles in pregnancy-related complications, offering more integrated information in maternal-fetal immunity.
Assuntos
Decídua/imunologia , Histocompatibilidade Materno-Fetal/imunologia , Macrófagos/imunologia , Complicações na Gravidez/imunologia , Trofoblastos/imunologia , Decídua/citologia , Feminino , Humanos , Tolerância Imunológica , GravidezRESUMO
Implantation of the embryo is a rate-limiting step for a successful pregnancy, and it requires an intricate crosstalk between the embryo and the endometrium. Extracellular vesicles (EVs) are membrane-enclosed, nano-sized structures produced by cells to mediate cell to cell communication and modulate a diverse set of biological processes. Herein, we review the involvement of EVs in the process of embryo implantation and endometrial diseases. EVs have been isolated from uterine fluid, cultured endometrial epithelial/stromal cells and trophectodermal cells. The endometrial epithelial and stromal/decidual cell-derived EVs and its cargo are internalized bythe trophoblast cells, and they regulate a diverse set of genes involved in adhesion, invasion and migration. Conversely, the embryo-derived EVs and its cargo are internalized by epithelial and immune cells of the endometrium for biosensing and immunomodulation required for successful implantation. EVs have also been shown to play a role in infertility, recurrent implantation failure, endometriosis, endometritis and endometrial cancer. Further research should set a stage for EVs as non-invasive "liquid biopsy" tools for assessment of endometrial health.
Assuntos
Endométrio/patologia , Vesículas Extracelulares/imunologia , Placenta/imunologia , Complicações na Gravidez/imunologia , Gravidez/imunologia , Trofoblastos/imunologia , Animais , Implantação do Embrião , Embrião de Mamíferos , Feminino , Humanos , Imunomodulação , Nanoestruturas , Complicações na Gravidez/patologiaRESUMO
OBJECTIVE: The present study was to estimate the role of cytokines for trophoblast death in NK cells presence. METHODS: This study involves assessment of NK-92 line NK cell cytotoxic activity against JEG-3 line cells, in presence of cytokines. We also assessed the effect of secretory placenta products on NK cell cytotoxic activity toward JEG-3 line cells. RESULTS: Uteroplacental contact zone cytokines are able to enhance trophoblast mortality both by themselves in case of IL-1ß, IL-6, IFNγ, IL-4, TGFß, bFGF, and also through increasing the cytotoxic potential of NK cells in case of IL-1ß, IFNγ, IL-8, TGFß, and GM-CSF. PLGF decreases NK cell cytotoxicity for trophoblasts. Secretory products of first trimester placenta enhance NK cell cytotoxic potential for trophoblasts. CONCLUSIONS: Cytokines of the uteroplacental contact zone can appear a mechanism ensuring trophoblast mortality dynamics throughout pregnancy.
Assuntos
Citocinas/farmacologia , Células Matadoras Naturais/efeitos dos fármacos , Trofoblastos/efeitos dos fármacos , Adolescente , Adulto , Comunicação Celular/efeitos dos fármacos , Comunicação Celular/imunologia , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/imunologia , Células Cultivadas , Citotoxicidade Imunológica/efeitos dos fármacos , Feminino , Humanos , Células K562 , Células Matadoras Naturais/fisiologia , Placenta/efeitos dos fármacos , Placenta/imunologia , Placenta/metabolismo , Gravidez , Primeiro Trimestre da Gravidez/efeitos dos fármacos , Primeiro Trimestre da Gravidez/imunologia , Primeiro Trimestre da Gravidez/metabolismo , Trofoblastos/imunologia , Trofoblastos/metabolismo , Útero/efeitos dos fármacos , Útero/imunologia , Útero/metabolismo , Adulto JovemRESUMO
During pregnancy, the maternal uterus and fetus form a special microenvironment at the maternal-fetal interface to support fetal development. Extravillous trophoblasts (EVTs), differentiated from the fetus, invade into the decidua and interact with maternal cells. Human leukocyte antigen (HLA)-G is a non-classical MHC-I molecule that is expressed abundantly and specifically on EVTs in physiological conditions. Soluble HLA-G (sHLA-G) is also found in maternal blood, amniotic fluid, and cord blood. The abnormal expression and polymorphisms of HLA-G are related to adverse pregnancy outcomes such as preeclampsia (PE) and recurrent spontaneous abortion (RSA). Here we summarize current findings about three main roles of HLA-G during pregnancy, namely its promotion of spiral artery remodeling, immune tolerance, and fetal growth, all resulting from its interaction with immune cells. These findings are not only of great significance for the treatment of pregnancy-related diseases but also provide clues to tumor immunology research since HLA-G functions as a checkpoint in tumors.
Assuntos
Microambiente Celular/imunologia , Antígenos HLA-G/imunologia , Histocompatibilidade Materno-Fetal , Troca Materno-Fetal/imunologia , Placenta/imunologia , Placenta/metabolismo , Animais , Biomarcadores , Desenvolvimento Embrionário/imunologia , Feminino , Regulação da Expressão Gênica no Desenvolvimento , Humanos , Tolerância Imunológica , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/metabolismo , Gravidez , Transdução de Sinais , Trofoblastos/imunologia , Trofoblastos/metabolismoRESUMO
In early equine pregnancy, a highly invasive trophoblast cell subpopulation, the chorionic girdle cells, invade the endometrium and form endometrial cups (EC). These cells express classical MHC molecules, thereby stimulating a humoral and cellular immune response, resulting in a massive accumulation of maternal CD4+ and CD8+ T cells around the EC. Nevertheless, no immediate destruction of endometrial cups by maternal lymphoid cells occurs, presumably due to immune tolerance. Although the environment of EC is rich in TGFB and in FOXP3+, CD4+ T cells, the mechanisms leading to tolerance have not been elucidated. Recently, we discovered that equine trophoblast cells secrete pregnancy-specific glycoproteins (PSGs). Since human and murine PSGs activate latent TGFB, we hypothesized that equine PSGs may have a similar activity. We performed plasmon surface resonance experiments to show that equine PSG CEACAM49 can directly bind to the latency-associated peptide (LAP) of both TGFB1 and TGFB2. We then found that the binding of CEACAM49 leads to the activation of TGFB1 as determined by both ELISA and cell-based assays. Furthermore, the activation of TGFB is a unique function of PSGs within the human CEA family, because CEACAM1, 3, 5, 6, 8 do not activate this cytokine. This finding further strengthens the classification of CEACAM49 as an equine PSG. Based on our results, we hypothesize that activation of latent TGFB in the EC environment by equine PSGs secreted by invasive trophoblast cells, could contribute to the generation of regulatory T cells (Tregs) to maintain immune tolerance.
Assuntos
Antígeno Carcinoembrionário/metabolismo , Endométrio/metabolismo , Glicoproteínas/metabolismo , Linfócitos T Reguladores/imunologia , Fator de Crescimento Transformador beta1/metabolismo , Trofoblastos/metabolismo , Animais , Endométrio/imunologia , Endométrio/patologia , Feminino , Cavalos , Gravidez , Fator de Crescimento Transformador beta1/genética , Trofoblastos/imunologia , Trofoblastos/patologiaRESUMO
New evidence suggests that glycan expression in placental cells of women with invasive disorders of pregnancy differs from that in normal pregnant women. Hypothesizing that modifications of glycan expression could account for the course of preeclampsia, we established placental villous histocultures and compared glycan expression in women with preeclampsia with that in normal pregnant women and also in syncytialized BeWo cells, and we tested the effect of glycan expression on the functional phenotypes of circulating natural killer (NK) cells. Histocultures of third-trimester placentae from women with preeclampsia and full-term placentae from healthy pregnant women and BeWo choriocarcinoma cells were assessed for the expression of terminal glycans by lectin-binding assays. Circulating NK cells from nonpregnant healthy donors were tested in vitro for their cytotoxic activity and intracellular cytokine content. Histocultures from women with preeclampsia expressed significantly more mannose than did those from healthy pregnant women. Both histocultures and BeWo cells expressed terminal fucose, mannose, sialic acid, and N -acetylgalactosamine, although mean fluorescence intensity (MFI) expression was lower in choriocarcinoma cells than in cells from histocultures. Cocultures of circulating NK cells with K562 target cells resulted in a dose-dependent cytotoxicity effect, but the use of BeWo cells as target reduced cytotoxic activity; this reduction was not affected by syncytialization. Histocultures of placental villous tissue of women with preeclampsia expressed high levels of terminal mannose. We proposethat placental glycans may modulate the functional activity of circulating NK cells in the context of systemic inflammatory response in preeclampsia.
Assuntos
Vilosidades Coriônicas/patologia , Células Matadoras Naturais/imunologia , Polissacarídeos/metabolismo , Pré-Eclâmpsia/imunologia , Adolescente , Adulto , Estudos de Casos e Controles , Comunicação Celular/imunologia , Linhagem Celular , Vilosidades Coriônicas/imunologia , Vilosidades Coriônicas/metabolismo , Feminino , Glicosilação , Voluntários Saudáveis , Humanos , Células Matadoras Naturais/metabolismo , Pré-Eclâmpsia/sangue , Pré-Eclâmpsia/patologia , Gravidez , Terceiro Trimestre da Gravidez , Estudos Prospectivos , Trofoblastos/imunologia , Trofoblastos/metabolismo , Adulto JovemRESUMO
BACKGROUD: Prostaglandin E2 (PGE2), an inflammatory mediator, modulates cytokines, regulates immune responses in reproductive processes and stimulates inflammatory reactions via the prostaglandin E2 receptor 2 (EP2). However, the regulatory effects of EP2 signaling on trophoblasts and its role in unexplained recurrent miscarriage (uRM) remains unclear. PATIENTS AND METHODS: A total of 19 placentas from patients with a history of more than two consecutive pregnancy losses of unknown cause (uRM group) and placentas of 19 healthy patients following a legal termination of their pregnancy were used for PGE2 receptor (EP1, EP2 and EP4) expression analyses via immunohistochemistry. Double immunofluorescence was also used to identify EP2 expressing cells in the decidua. Finally, HTR-8/SVneo cells were used to clarify the role of EP2 in in vitro experiments. RESULTS: The expression of EP2 and EP4 was found to be reduced in the syncytiotrophoblast and decidua of uRM patients. A selective EP2 receptor antagonist (PF-04,418,948) reduced the proliferation and secretion of ß-hCG, inhibited interleukin -6 (IL-6) and interleukin-8 (IL-8) and up-regulated the production of the tumor necrosis factor-α (TNF-α) and plasminogen activator inhibitor type 1 (PAI-1) in HTR-8/SVneo cells in vitro. CONCLUSION: PGE2-EP2 signaling pathway may represent a novel therapy option for uRM. The involvement of EP2 in uRM acts perhaps via inflammatory cytokines and indicates that the PGE2-EP2 signaling pathway might represent an unexplored etiology for uRM.