Abortions are the most important reason for unintentional childlessness. During pregnancy, maternal immune cells are in close contact to cells of the semi-allogeneic fetus. Dysregulation of the maternal immune system leading to defective adaptation to pregnancy often plays a role in pathogenesis of abortions. Myeloid-derived suppressor cells (MDSC) are myeloid cells that suppress functions of other immune cells, especially T-cells, thereby negatively affecting diseases such as cancer, sepsis or trauma. They seem, however, also necessary for maintenance of maternal-fetal tolerance. Mechanisms regulating MDSC expansion and function during pregnancy are only incompletely understood. In tumor environment, hypoxia is crucial for MDSC accumulation and activation. Hypoxia is also important for early placenta and embryo development. Effects of hypoxia are mediated through hypoxia-inducible factor 1α (HIF-1α). In the present study we aimed to examine the role of HIF-1α in myeloid cells for MDSC accumulation and MDSC function during pregnancy and for pregnancy outcome. We therefore used a mouse model with targeted deletion of HIF-1α in myeloid cells (myeloid HIF-KO) and analyzed blood, spleens and uteri of pregnant mice at gestational day E 10.5 in comparison to non-pregnant animals and wildtype (WT) animals. Further we analyzed pregnancy success by determining rates of failed implantation and abortion in WT and myeloid HIF-KO animals. We found that myeloid HIF-KO in mice led to an abrogated MDSC accumulation in the pregnant uterus and to impaired suppressive activity of MDSC. While expression of chemokine receptors and integrins on MDSC was not affected by HIF-1α, myeloid HIF-KO led to increased apoptosis rates of MDSC in the uterus. Myeloid-HIF-KO resulted in increased proportions of non-pregnant animals after positive vaginal plug and increased abortion rates, suggesting that activation of HIF-1α dependent pathways in MDSC are important for maintenance of pregnancy.

Background: Sepsis is a major cause of death in neonates. Knowledge about epidemiology, risk factors, causative pathogens and outcome of neonatal sepsis is important to improve neonatal care. For Germany, only few data on neonatal sepsis in very low birth weight (VLBW) infants exist. Methods: Data from 14,926 preterm infants with birth weight <1500 g and gestational age between 22 0/7 weeks and 31 6/7 collected between January 2009 and December 2017 were analyzed for frequency of early-onset sepsis (EOS) and late-onset sepsis (LOS) and for causative pathogens. Risk factors for the development of EOS and LOS and outcomes after EOS and LOS were analyzed by multivariate logistic regression models. Results: EOS occurred in 1.1% of infants and LOS in 11.9%. Escherichia coli was the most common pathogen in EOS, coagulase-negative staphylococci in LOS. Multidrug-resistant organisms were detected in 8.4% of EOS and 3.9% of LOS cases. Risk factors for EOS were lower gestational age, intra-amniotic infection and spontaneous delivery. Risk factors for LOS were lower gestational age, small for gestational age, central lines, endotracheal ventilation and history of EOS. Both EOS and LOS were independently associated with adverse neonatal outcome. Conclusions: These data from a large German neonatal cohort confirm neonatal sepsis as the most common cause of morbidity and mortality in VLBW infants, as well as E. coli and coagulase-negative staphylococci as the most prevalent pathogens. Multidisciplinary approaches such as antibiotic stewardship, hygiene and feeding strategies are necessary to further reduce the burden of sepsis in VLBW infants.

Neutrophils are classically characterized as merely reactive innate effector cells. However, the microbiome is known to shape the education and maturation process of neutrophils, improving their function and immune-plasticity. Recent reports demonstrate that murine neutrophils possess the ability to exert adaptive responses after exposure to bacterial components such as LPS (Gram-negative bacteria) or LTA (Gram-positive bacteria). We now ask whether small extracellular vesicles (EVs) from the gut may directly mediate adaptive responses in neutrophils in vitro. Murine bone marrow-derived neutrophils were primed in vitro by small EVs of high purity collected from colon stool samples, followed by a second hit with LPS. We found that low-dose priming with gut microbiota-derived small EVs enhanced pro-inflammatory sensitivity as indicated by elevated levels of TNF-α, IL-6, ROS and MCP-1 and increased migratory and phagocytic activity. In contrast, high-dose priming resulted in a tolerant phenotype, marked by increased IL-10 and decreased transmigration and phagocytosis. Alterations in TLR2/MyD88 as well as TLR4/MyD88 signaling were correlated with the induction of adaptive cues in neutrophils in vitro. Taken together, our study shows that small EVs from stools can drive adaptive responses in neutrophils in vitro and may represent a missing link in the gut–immune axis.