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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. A novel group of non‐classical microRNAs (miR‐21a, miR‐29a, miR‐146a‐3p, Let‐7b) function as endogenous danger signals by activating the ssRNA viral sensors TLR7 and TLR8. In this study, the pro‐inflammatory roles of TLR7/TLR8‐activating miRs were examined as mediators of FM inflammation in response to bacterial lipopolysaccharide (LPS) using an in vitro human FM explant system, an in vivo mouse model of pregnancy, and human clinical samples. Following LPS exposure, miR‐146a‐3p was significantly increased in both human FM explants and wild‐type mouse FMs. Expression of miR‐146a‐3p was also significantly elevated in FMs from women with preterm birth and chorioamnionitis. FM IL‐8 and inflammasome‐mediated IL‐1β production in response to LPS was dependent on miR‐146a‐3p and TLR8 downstream of TLR4 activation. In wild‐type mice, LPS exposure increased FM IL‐8 and IL‐1β production and induced preterm birth. In TLR7−/−/TLR8−/− mice, LPS exposure was able to initiate but not sustain preterm birth, and FM inflammation was reduced. Together, we demonstrate a novel signalling mechanism at the maternal‐fetal interface in which TLR8‐activating miR‐146a‐3p acts as an intermediate danger signal to drive FM inflammasome‐dependent and ‐independent mechanisms of inflammation and, thus, may play a role in chorioamnionitis and subsequent preterm birth. [ABSTRACT FROM AUTHOR]

ProblemDiabetes confers an increased risk of preeclampsia, but its pathogenic role in preeclampsia is poorly understood. The objective of this study was to elucidate the effects of excess glucose on trophoblast function and whether any changes could be reversed by metformin.Method of studyThe human first trimester trophoblast cell line (Sw.71) was treated with glucose at 5, 10, 25, and 50 mm, in the presence and absence of metformin. Trophoblast migration was quantified and supernatant cytokine, chemokine, and angiogenic factors measured.ResultsIncreasing concentrations of glucose significantly increased trophoblast secretion of the inflammatory cytokines/chemokines: IL-1β, IL-6, IL-8, GRO-α, RANTES, and G-CSF; significantly increased trophoblast secretion of the anti-angiogenic factors sFlt-1 and sEndoglin; and significantly decreased trophoblast migration. Excess glucose-induced trophoblast IL-1β production was inhibited by disabling the Nalp3/ASC inflammasome. Metformin partially reduced the glucose-induced inflammatory response, but had no effect on the anti-angiogenic or antimigratory response.ConclusionExcess glucose induced a pro-inflammatory, anti-angiogenic, and antimigratory state in first trimester trophoblast cells. Glucose-induced trophoblast IL-1β secretion was mediated by the inflammasome. Glucose-induced inflammation was partially reversed by metformin. These findings demonstrate the pleiotropic effects of hyperglycaemia on the trophoblast, providing potential explanations for the strong link between diabetes and preeclampsia.

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. [ABSTRACT FROM AUTHOR]

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. Thus, appropriate decidualization and EnSC function is key for establishment of a successful pregnancy. This study was undertaken to explore the effects of aPL on EnSC decidualization, senescence, and inflammation. Methods: EnSCs under decidualizing conditions were exposed to aPL or control IgG alone or in the presence of either a Toll‐like receptor 4 (TLR‐4) antagonist, a p38 MAPK inhibitor, a reactive oxygen species (ROS) inhibitor, low molecular weight heparin (LMWH), or acetyl salicylic acid. Secretion of decidualization markers and inflammatory interleukin‐8 were quantified by enzyme‐linked immunosorbent assay, and senescence‐associated β‐galactosidase activity was evaluated. In a mouse model of decidualization, aPL or control IgG was administered, and uterine expression levels of decidualization and inflammatory markers were quantified by real‐time quantitative polymerase chain reaction. Results: Antiphospholipid antibodies increased human EnSC decidualization, senescence, and inflammation. This phenotype was recapitulated in the mouse model. The decidualization and inflammatory responses were partially mediated by TLR‐4 and p38 MAPK, while the decidualization and senescence responses were ROS‐dependent. LMWH, commonly used to treat aPL‐positive women at risk of obstetric complications, reduced the ability of aPL to increase EnSC decidualization and inflammation. Conclusion: These findings shed new light on the pathogenesis of pregnancy complications in women with aPLs and underscore the benefit of heparin in preventing pregnancy loss in this high‐risk population. [ABSTRACT FROM AUTHOR]

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. The goal of this study was to characterize the effect of viral components on trophoblast responses to aPL. Method of study: A human first trimester trophoblast cell line was treated with or without aPL or control IgG in the presence of media, viral dsRNA or viral ssRNA. Supernatants were measured for inflammatory IL‐1β and IL‐8; inflammasome‐associated uric acid and caspase‐1 activity; and anti‐angiogenic sFlt‐1. Trophoblast migration was measured using a two‐chamber assay. Results: Viral dsRNA augmented aPL‐induced trophoblast caspase‐1 activity, and IL‐1β and IL‐8 secretion in an additive manner. Viral ssRNA inhibited aPL‐induced uric acid, IL‐1β and sFlt‐1 secretion, and further exacerbated aPL‐inhibition of trophoblast migration. Conclusion: While viral ssRNA may have some protective effects on aPL‐induced inflammation and anti‐angiogenic responses, viral dsRNA exacerbated aPL‐mediated inflammation and viral ssRNA further limited cell migration, which could prove detrimental to placentation. Thus, viral infections may contribute to adverse pregnancy outcomes in women with aPL. [ABSTRACT FROM AUTHOR]