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Human Reproduction Update Sep 2023The endometrium is a highly dynamic tissue that undergoes dramatic proliferation and differentiation monthly in order to prepare the uterus for implantation and... (Review)
Review
BACKGROUND
The endometrium is a highly dynamic tissue that undergoes dramatic proliferation and differentiation monthly in order to prepare the uterus for implantation and pregnancy. Intrauterine infection and inflammation are being increasingly recognized as potential causes of implantation failure and miscarriage, as well as obstetric complications later in gestation. However, the mechanisms by which the cells of the endometrium respond to infection remain understudied and recent progress is slowed in part owing to similar overlapping studies being performed in different species.
OBJECTIVE AND RATIONALE
The aim of this scoping review is to systematically summarize all published studies in humans and laboratory animals that have investigated the innate immune sensing and response of the endometrium to bacteria and viruses, and the signaling mechanisms involved. This will enable gaps in our knowledge to be identified to inform future studies.
SEARCH METHODS
The Cochrane Library, Ovid Embase/Medline, PubMed, Scopus, Google Scholar, and Web of Science databases were searched using a combination of controlled and free text terms for uterus/endometrium, infections, and fertility to March 2022. All primary research papers that have reported on endometrial responses to bacterial and viral infections in the context of reproduction were included. To focus the scope of the current review, studies in domesticated animals, included bovine, porcine, caprine, feline, and canine species were excluded.
OUTCOMES
This search identified 42 728 studies for screening and 766 full-text studies were assessed for eligibility. Data was extracted from 76 studies. The majority of studies focused on endometrial responses to Escherichia coli and Chlamydia trachomatis, with some studies of Neisseria gonorrhea, Staphylococcus aureus, and the Streptococcus family. Endometrial responses have only been studied in response to three groups of viruses thus far: HIV, Zika virus, and the herpesvirus family. For most infections, both cellular and animal models have been utilized in vitro and in vivo, focusing on endometrial production of cytokines, chemokines, and antiviral/antimicrobial factors, and the expression of innate immune signaling pathway mediators after infection. This review has identified gaps for future research in the field as well as highlighted some recent developments in organoid systems and immune cell co-cultures that offer new avenues for studying endometrial responses to infection in more physiologically relevant models that could accelerate future findings in this area.
WIDER IMPLICATIONS
This scoping review provides an overarching summary and benchmark of the current state of research on endometrial innate immune responses to bacterial and viral infection. This review also highlights some exciting recent developments that enable future studies to be designed to deepen our understanding of the mechanisms utilized by the endometrium to respond to infection and their downstream effects on uterine function.
Topics: Pregnancy; Female; Animals; Cattle; Cats; Dogs; Humans; Swine; Goats; Endometrium; Uterus; Bacteria; Virus Diseases; Zika Virus; Zika Virus Infection
PubMed: 37290428
DOI: 10.1093/humupd/dmad013 -
Environmental Research Jul 2023Placenta mediates the transfer of nutrients, oxygen and drugs from mother to fetus. It is constituted by two cellular layers separated by the intervillous space: the...
Placenta mediates the transfer of nutrients, oxygen and drugs from mother to fetus. It is constituted by two cellular layers separated by the intervillous space: the outer is in direct contact with maternal blood (decidua placenta), and the inner (villi) directly in contact with the fetus. Environmental contaminants, such as per- and polyfluoroalkyl substances (PFAS) also demonstrated the ability to cross the tissue multiple layers, posing at risk the health of the fetus. The aim of the present study was to analyse the PFAS amount in decidua and villi placenta explants and to study differences in their distribution among the two side of this organ. The determination of 23 PFAS was carried out by liquid chromatography coupled to high-resolution accurate mass spectrometry (LC-HRAM). Our research included women who delivered at term between 2021 and 2022. Our data indicated that all samples contained at least one PFAS, demonstrating the ubiquitarian presence of these compounds in our population. A high occurrence of PFOS, PFOA and PFHxS, followed by PFHxA, PFBS and PFUnA was found. The fluorotelomer 6:2 FTS was also present in more than 40% of samples and this represent the first data on placenta explants. Mean and median PFAS values for decidual explants were 0.5 ng/g and 0.4 ng/g (SD 0.3), while for villi explants mean and median values were 0.6 ng/g and 0.4 ng/g (SD 0.4). A different pattern of accumulation was observed between villi and decidual explants for PFOS, PFOA and PFUnA (villi > decidua) and PFHxA, PFHxS, PFBS and 6:2 FTS (decidua > villi). Even if the mechanism of this selectively accumuation is not yet understood, molecular degree of ionization and its lipophilicity could at least in part explain this difference. This study expands the limited data describing PFAS levels in the placenta and pose attention on PFAS exposure during pregnancy.
Topics: Pregnancy; Humans; Female; Placenta; Fluorocarbons; Mothers; Decidua; Alkanesulfonic Acids; Environmental Pollutants
PubMed: 37119845
DOI: 10.1016/j.envres.2023.115955 -
Nature Communications Nov 2023The timely onset of female parturition is a critical determinant for pregnancy success. The highly heterogenous maternal decidua has been increasingly recognized as a...
The timely onset of female parturition is a critical determinant for pregnancy success. The highly heterogenous maternal decidua has been increasingly recognized as a vital factor in setting the timing of labor. Despite the cell type specific roles in parturition, the role of the uterine epithelium in the decidua remains poorly understood. This study uncovers the critical role of epithelial SHP2 in parturition initiation via COX1 and COX2 derived PGF2α leveraging epithelial specific Shp2 knockout mice, whose disruption contributes to delayed parturition initiation, dystocia and fetal deaths. Additionally, we also show that there are distinct types of epithelium in the decidua approaching parturition at single cell resolution accompanied with profound epithelium reformation via proliferation. Meanwhile, the epithelium maintains the microenvironment by communicating with stromal cells and macrophages. The epithelial microenvironment is maintained by a close interaction among epithelial, stromal and macrophage cells of uterine stromal cells. In brief, this study provides a previously unappreciated role of the epithelium in parturition preparation and sheds lights on the prevention of preterm birth.
Topics: Animals; Female; Humans; Infant, Newborn; Mice; Pregnancy; Biochemical Phenomena; Labor, Obstetric; Parturition; Premature Birth; Uterus
PubMed: 37963860
DOI: 10.1038/s41467-023-43102-8 -
Nature Communications Nov 2023Tissue-resident Natural Killer (trNK) cells are crucial components of local immunity that activate rapidly upon infection. However, under steady state conditions, their...
Tissue-resident Natural Killer (trNK) cells are crucial components of local immunity that activate rapidly upon infection. However, under steady state conditions, their responses are tightly controlled to prevent unwanted tissue damage. The mechanisms governing their differentiation and activation are not fully understood. Here, we characterise uterine trNK cells longitudinally during pregnancy by single cell RNA sequencing and find that the combined expression pattern of 4-1BB and CD55 defines their three distinct stages of differentiation in mice. Mechanistically, an IL-21R-STAT3 axis is essential for initiating the trNK cell differentiation. The fully differentiated trNK cells demonstrate enhanced functionality, which is necessary for remodelling spiral arteries in the decidua. We identify an apoptotic program that is specific to the terminal differentiation stage, which may preclude tissue damage by these highly activated trNK cells. In summary, uterine trNK cells become intensely active and effective during pregnancy, but tightly controlled via a differentiation program that also limits potential harm, suggesting an intricate mechanism for harnessing trNK cells in maintaining pregnancy.
Topics: Animals; Female; Mice; Pregnancy; Cell Differentiation; Killer Cells, Natural; Transcription Factors; Uterus; Receptors, Interleukin-21; STAT3 Transcription Factor; Signal Transduction
PubMed: 37925507
DOI: 10.1038/s41467-023-42990-0 -
Medicine International 2024Subchorionic hematoma (SCH) is a hematoma in which blood accumulates between the chorion and decidua basalis due to the separation of the chorion and decidua basalis. It... (Review)
Review
Subchorionic hematoma (SCH) is a hematoma in which blood accumulates between the chorion and decidua basalis due to the separation of the chorion and decidua basalis. It is common in patients with threatened abortion in early pregnancy and is mainly detected by ultrasound. SCH mainly manifests as an hypoechoic or anechoic crescent-shaped fluid dark area on ultrasound images. Although there are numerous studies on SCH, its pathogenesis and etiology remain unclear, and its influence on pregnancy outcomes is also controversial; there are also no uniform clinical treatment guidelines. Current studies suggest that the occurrence of SCH may be related to several factors, such as abnormal coagulation function, autoimmune factors of pregnant women, assisted reproduction, drug use during pregnancy and reproductive tract infection; however, its exact etiology remains unclear. Some studies suggest that SCH is associated with adverse pregnancy outcomes such as miscarriage, preterm birth, preeclampsia and fetal growth restriction, although other studies have found that SCH does not increase the risk of adverse pregnancy outcomes. Therefore, the present review mainly discusses the pathogenesis, etiology and treatment of SCH in an aim to provide a reference for the clinical treatment of this condition in pregnant women.
PubMed: 38362561
DOI: 10.3892/mi.2024.134 -
Cureus Jun 2024Pregnancy is a highly regulated biological phenomenon that involves the development of a semi-allogeneic fetus inside the uterus of the mother. The maternal-fetal... (Review)
Review
Pregnancy is a highly regulated biological phenomenon that involves the development of a semi-allogeneic fetus inside the uterus of the mother. The maternal-fetal interface is a critical junction where communication takes place between the fetal and maternal immune systems, which determine the outcome of the pregnancy. The interface is composed of the decidua and placenta. The main cells present at the maternal-fetal interface include invading trophoblasts, maternal immune cells, and decidual stromal cells. Although maternal tolerance is crucial for maintaining a successful pregnancy, the role of the placenta in pregnancy is also important. Dysregulation of the placenta leads to various placenta-mediated complications, such as preeclampsia, intrauterine growth restriction, and placental abruption. Although the exact mechanism involving these complications is unclear, research has elucidated various factors involved in these pregnancy disorders. This review aimed to provide a summary of the maternal-fetal interface and immune mechanisms involved in placenta-mediated complications.
PubMed: 38882223
DOI: 10.7759/cureus.62457 -
Redox Biology Nov 2023Myeloperoxidase (MPO) is one of the most abundant proteins in neutrophil granules. It catalyzes the production of reactive oxygen species, which are important in...
Myeloperoxidase (MPO) is one of the most abundant proteins in neutrophil granules. It catalyzes the production of reactive oxygen species, which are important in inflammation and immune defense. MPO also binds to several proteins, lipids, and DNA to alter their function. MPO is present at the feto-maternal interface during pregnancy, where neutrophils are abundant. In this study, we determined the effect of MPO on JEG-3 human choriocarcinoma cells as a model of extravillous trophoblasts (EVTs) during early pregnancy. We found that MPO was internalized by JEG-3 cells and localized to the cytoplasm and nuclei. MPO internalization and activity enhanced JEG-3 cell migration and invasion, whereas this effect was impaired by pre-treating cells with heparin, to block cellular uptake, and MPO-activity inhibitor 4-ABAH. This study identifies a novel mechanism for the effect of MPO on EVT function during normal pregnancy and suggests a potential role of MPO in abnormal pregnancies.
Topics: Female; Humans; Pregnancy; Cell Line, Tumor; Choriocarcinoma; Peroxidase; Proteins; Trophoblasts
PubMed: 37776707
DOI: 10.1016/j.redox.2023.102885 -
Frontiers in Immunology 2023Placental trophoblasts contribute to regulatory T (Treg) function the programmed cell death-1 (PD-1)/PD-1 ligand 1 (PD-L1) pathway during normal pregnancy. Decreased...
INTRODUCTION
Placental trophoblasts contribute to regulatory T (Treg) function the programmed cell death-1 (PD-1)/PD-1 ligand 1 (PD-L1) pathway during normal pregnancy. Decreased expression of PD-L1 in trophoblasts was closely associated with Treg deficiency in the development of pregnancy failure. Thus, targeting PD-L1 might be a novel therapy to prevent pregnancy loss. However, the mechanisms for modulating the expression of PD-L1 in trophoblasts are an enigma.
METHODS
The proportion of decidual Treg cells, and the profile of decidual macrophages (DMs) sampled from women with normal pregnancy (NP) and recurrent miscarriage (RM) were evaluated by flow cytometry. The expression of Yin and Yang 1 protein (YY1) and PD-L1 in human villous were measured by Immunohistochemistry (IHC), qRT-PCR and western blot. The determination of soluble PD-L1 (sPD-L1) in serum from NP and RM, and trophoblast conditioned media (TCM) was performed by the PD-L1 SimpleStep ELISA kit. Knockdown of YY1 was processed in the human trophoblast derived cell lines, HTR-8 and Bewo, with siYY1 transfection. Peripheral naïve CD4 T cells were isolated from women with NP for the culture. The percentages of Treg cells differentiated from peripheral naïve CD4 T cells were measured by flow cytometry. The interaction between YY1 and was proved by CHIP. The expression of inducible nitric oxide synthase (iNOS) in decidua was evaluated by IHC. The level of NO in serum from women with NP and RM was determined by the Griess reagent system. The effects of NO on YY1 were determined by the culture of HTR-8 cells with the NO donor, SNAP. The model comprising twelve pregnant mice and underwent different treatment. The percentages of Treg cells in murine uterus were measured by flow cytometry. Similarly, Western blot and IHC were performed to determine the expression of YY1 and PD-L1 in murine placenta.
RESULTS
Decreased expression of YY1 and PD-L1 in trophoblasts and lower proportion of decidual Treg cells were observed in patients with RM. Knockdown of YY1 contributes to a lower expression of YY1 and PD-L1. Soluble PD-L1 in the supernatant from HTR-8 cells was also decreased with siYY1 administration. Lower Treg differentiation was observed in the presence of supernatant from HTR-8 cells treated with siYY1. CHIP analysis revealed that endogenous YY1 directly occupied the promoter region of the (PD-L1) gene. Accompanied with increased M1 DMs, higher NO was observed in serum sampled from patients with RM. In the presence of Reduced expression of YY1 and PD-L1 was observed in HTR-8 cells with the treatment of SNAP. Furthermore, less Treg differentiation was observed with SNAP treated TCM. Moreover, our data found that YY1 deficiency was associated with decreased PD-L1, which further resulting in less Treg differentiation and Treg deficiency at the maternal-fetal interface and increased embryo loss.
DISCUSSION
Our work found the modulatory capacity of YY1 on PD-L1 in trophoblasts during early pregnancy. Furthermore, reduced YY1 was supposed resulting from higher levels of NO produced from the M1 DMs in RM.
Topics: Animals; Female; Humans; Mice; Pregnancy; Abortion, Habitual; B7-H1 Antigen; Macrophages; Placenta; Programmed Cell Death 1 Receptor; T-Lymphocytes, Regulatory; Trophoblasts
PubMed: 37520550
DOI: 10.3389/fimmu.2023.1180154 -
Cell Reports Jul 2023Leukocyte diversity of the first-trimester maternal-fetal interface has been extensively described; however, the immunological landscape of the term decidua remains...
Leukocyte diversity of the first-trimester maternal-fetal interface has been extensively described; however, the immunological landscape of the term decidua remains poorly understood. We therefore profiled human leukocytes from term decidua collected via scheduled cesarean delivery. Relative to the first trimester, our analyses show a shift from NK cells and macrophages to T cells and enhanced immune activation. Although circulating and decidual T cells are phenotypically distinct, they demonstrate significant clonotype sharing. We also report significant diversity within decidual macrophages, the frequency of which positively correlates with pregravid maternal body mass index. Interestingly, the ability of decidual macrophages to respond to bacterial ligands is reduced with pregravid obesity, suggestive of skewing toward immunoregulation as a possible mechanism to safeguard the fetus against excessive maternal inflammation. These findings are a resource for future studies investigating pathological conditions that compromise fetal health and reproductive success.
Topics: Pregnancy; Female; Humans; Decidua; T-Lymphocytes; Reproduction; Killer Cells, Natural; Macrophages
PubMed: 37432849
DOI: 10.1016/j.celrep.2023.112769