Buprenorphine Induces Human Fetal Membrane Sterile Inflammation.

Opioid-use disorder (OUD) during pregnancy has increased in the United States to critical levels and is a leading cause of maternal morbidity and mortality. Untreated OUD is associated with pregnancy complications in particular, preterm birth. Medications for OUD, such as buprenorphine, are recommended with the added benefit that treatment during pregnancy increases treatment post-partum.

Quantitative proteomics reveals differential extracellular vesicle cargo from M1 and M2 monocyte-derived human macrophages.

Extracellular vesicles (EVs) mediate intercellular communication by carrying molecular cargo that facilitate diverse physiological processes. Macrophages, playing central roles in immune responses, release EVs that modulate various cellular functions. Given the distinct roles of M1 and M2 macrophage states, understanding the proteomic profiles of their EVs is important for elucidation of EV-mediated signalling and identifying potential biomarkers for diseases involving macrophage polarisation.

Predictors of Inflammation-Mediated Preterm Birth.

Preterm birth remains a worldwide health concern because of ongoing challenges in prediction and prevention. Current predictors are limited by poor performance, need for invasive sampling, and an inability to identify patients in a timely fashion to allow for effective intervention. The multiple etiologies of preterm birth often have an inflammatory component.

Antiphospholipid-exposed trophoblast-derived extracellular vesicles express elevated levels of TLR7/8-activating microRNAs and induce endometrial endothelial activation, in part, through TLR7.

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.

TLR8-activating miR-146a-3p is an intermediate signal contributing to fetal membrane inflammation in response to bacterial LPS.

Preterm birth is the largest contributor to neonatal morbidity and is often associated with chorioamnionitis, defined as inflammation/infection of the fetal membranes (FMs). Chorioamnionitis is characterised by neutrophil infiltration of the FMs and is associated with elevated levels of the neutrophil chemoattractant, interleukin (IL)-8 and the proinflammatory cytokine, IL-1β. While FMs can respond to infections through innate immune sensors, such as toll-like receptors (TLRs), the downstream mechanisms by which chorioamnionitis arises are not fully understood.

Decidualization dampens toll-like receptor mediated inflammatory responses in human endometrial stromal cells by upregulating IκBα.

Endometrial stromal cells (EnSCs) are the major cell type of the human endometrium and they undergo dramatic differentiation, termed decidualization, every month that enables them to be receptive to implantation. Appropriate decidualization and EnSC function is key for a successful pregnancy. EnSC function may be affected when the uterus is exposed to bacterial and viral infection.

Endometrial responses to bacterial and viral infection: a scoping 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.

Cell-free fetal DNA impairs trophoblast migration in a TLR9-dependent manner and can be reversed by hydroxychloroquine.

Growing evidence suggests a relationship between elevated circulating placental-derived cell-free fetal DNA (cffDNA) and preeclampsia. Hypomethylation of CpG motifs, a hallmark of cffDNA, allows it to activate Toll-like receptor 9 (TLR9). Using an in vitro human first trimester extravillous trophoblast cell model, we sought to determine if trophoblast-derived cffDNA and ODN 2216, a synthetic unmethylated CpG oligodeoxynucleotide, directly impacted spontaneous trophoblast migration.

Distinct non-coding RNA cargo of extracellular vesicles from M1 and M2 human primary macrophages.

Macrophages are important antigen presenting cells which can release extracellular vesicles (EVs) carrying functional cargo including non-coding RNAs. Macrophages can be broadly classified into M1 'classical' and M2 'alternatively-activated' macrophages. M1 macrophages have been linked with inflammation-associated pathologies, whereas a switch towards an M2 phenotype indicates resolution of inflammation and tissue regeneration.

The serotonin reuptake inhibitor fluoxetine induces human fetal membrane sterile inflammation through p38 MAPK activation.

Serotonin Reuptake Inhibitors (SRIs) are often used as first line therapy for depression and other psychiatric disorders. SRI use during pregnancy is associated with preterm premature rupture of membranes (PPROM) and subsequent preterm birth. The objective of this study was to investigate the mechanism(s) responsible for SRI-associated PPROM.

Placental macrophage responses to viral and bacterial ligands and the influence of fetal sex.

Bacterial and viral infections of the placenta are associated with inflammation and adverse pregnancy outcomes. Hofbauer cells (HBCs) are fetal-origin macrophages in the placenta, proposed to protect the fetus from vertical pathogen transmission. We performed quantitative proteomics on term HBCs under resting conditions and following exposure to bacterial and viral pathogen-associated molecular patterns (PAMPs), and investigated the contribution of fetal sex.

Maternal selection of human embryos in early gestation: Insights from recurrent miscarriage.

Compared to most mammals, human pregnancy is unusual in that it involves chromosomally diverse embryos, cyclical breakdown and regeneration of the uterine mucosa, and intimate integration of fetal and maternal cells at the uteroplacental interface. Not surprisingly, pregnancy often falters in early gestation. Whether these losses result in clinical miscarriages depends on the origins and impacts of chromosomal errors on fetal development and the ability of the decidualizing endometrium to engage in embryo biosensing and selection.

Antiphospholipid Antibodies Increase Endometrial Stromal Cell Decidualization, Senescence, and Inflammation via Toll-like Receptor 4, Reactive Oxygen Species, and p38 MAPK Signaling.

Objective: Miscarriage affects 1 in 7 pregnancies, and antiphospholipid autoantibodies (aPLs) are one of the biggest risk factors for recurrent pregnancy loss. While aPLs target the endometrial stroma, little is known about their impact. Endometrial stromal cells (EnSCs) undergo decidualization each menstrual cycle, priming the uterus to receive implanting embryos.

Antiphospholipid Antibodies From Women With Pregnancy Morbidity and Vascular Thrombosis Induce Endothelial Mitochondrial Dysfunction, mTOR Activation, and Autophagy.

Antiphospholipid syndrome (APS) is an autoimmune disease characterized by thrombosis and pregnancy morbidity (PM) obstetric events together with persistent high titers of circulating antiphospholipid antibodies (aPL). Several mechanisms that explain the development of thrombosis and PM in APS include the association of aPL with alterations in the coagulation cascade and inflammatory events. Other mechanisms disturbing cellular homeostases, such as mitochondrial dysfunction, autophagy, and cell proliferation, have been described in other autoimmune diseases.

Antiphospholipid antibody-induced trophoblast responses are differentially modulated by viral dsRNA and viral ssRNA.

Problem: Women with antiphospholipid antibodies (aPL) are at increased risk for pregnancy loss and preeclampsia. aPL target the trophoblast and induce a pro-inflammatory, anti-angiogenic and anti-migratory profile. Since infection during pregnancy can increase the risk for preeclampsia, a viral infection could further increase this in women with aPL.

Human fetal membrane IL-1β production in response to bacterial components is mediated by uric-acid induced NLRP3 inflammasome activation.

Inflammatory interleukin-1β (IL-1β) is an important mediator of preterm birth. IL-1β secretion is mediated by the inflammasome that processes pro-IL-1β into its active form. However the mechanisms involved at the level of the fetal membrane (FM) are not fully understood.

Protein Phosphatase 2A Activation Via ApoER2 in Trophoblasts Drives Preeclampsia in a Mouse Model of the Antiphospholipid Syndrome.

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Visualization and Quantification of Neutrophil Extracellular Traps.

Neutrophils are innate immune cells that play important roles in many physiological and pathological processes, including immune defense and cancer metastasis. In addition to the release of proinflammatory cytokines, chemokines, and cytoplasmic granules containing digestive proteins, in recent years, neutrophils have been observed to release neutrophil extracellular traps (NETs) that consist of extracellular DNA associated with antimicrobial proteins, such as histones and myeloperoxidase. These NETs are increasingly being recognized as an important mechanism of neutrophil host defense and function.

Recurrent miscarriage: evidence to accelerate action.

Women who have had repeated miscarriages often have uncertainties about the cause, the likelihood of recurrence, the investigations they need, and the treatments that might help. Health-care policy makers and providers have uncertainties about the optimal ways to organise and provide care. For this Series paper, we have developed recommendations for practice from literature reviews, appraisal of guidelines, and a UK-wide consensus conference that was held in December, 2019.

Polymicrobial stimulation of human fetal membranes induce neutrophil activation and neutrophil extracellular trap release.

Preterm birth is a major contributor to neonatal mortality and morbidity. While the causes of preterm birth remain incompletely understood, infection is a major risk factor, and chorioamnionitis is commonly observed. Chorioamnionitis is characterized by inflammation and neutrophil infiltration of the fetal membranes (FM).

Activated Neutrophils Propagate Fetal Membrane Inflammation and Weakening through ERK and Neutrophil Extracellular Trap-Induced TLR-9 Signaling.

Preterm birth is associated with significant neonatal mortality and morbidity worldwide. Chorioamnionitis, inflammation of the fetal membranes (FMs), is a major risk factor and is characterized by neutrophil infiltration. However, the role of neutrophils at the FMs remains unclear.

Acetaminophen Attenuates invasion and alters the expression of extracellular matrix enzymes and vascular factors in human first trimester trophoblast cells.

Acetaminophen is one of the most common medications taken during pregnancy, considered safe for maternal health and fetal development. However, recent epidemiological studies have associated prenatal acetaminophen use with several developmental disorders in offspring. As acetaminophen can freely cross into and through the placenta, epidemiological associations with prenatal acetaminophen use may reflect direct actions on the fetus and/or the impact of altered placental functions.

Neutrophils in preterm birth: Friend or foe?

Preterm birth is a serious global health problem that affects 5-18% of pregnancies worldwide. In addition to being the major cause of neonatal mortality and morbidity, preterm birth is associated with short term and long term complications in the offspring. Despite this, the causes and pathogenesis of preterm birth remain unclear.

NLRP3 inflammasome function and pyroptotic cell death in human placental Hofbauer cells.

Alterations in the number and protein/gene expression of Hofbauer cells (HBCs) may play a role in microbial-driven/cytokine-mediated placental inflammation, and in subsequent pregnancy complications such as villitis, histologic chorioamnionitis, and the fetal inflammatory response syndrome. Pyroptosis is an inflammatory form of cell death mediated by the inflammasome, a multi-protein complex which drives the processing and secretion of interleukin 1 beta (IL-1β). Pyroptosis can be triggered by bacterial lipopolysaccharide (LPS) and adenosine triphosphate (ATP) in non-placental macrophages through activation of the NLRP3 inflammasome.