Maternal obesity blunts antimicrobial responses in fetal monocytes

Abstract

Maternal pre-pregnancy (pregravid) obesity is associated with adverse outcomes for both mother and offspring. Amongst the complications for the offspring is increased susceptibility and severity of neonatal infections necessitating admission to the intensive care unit, notably bacterial sepsis and enterocolitis. Previous studies have reported aberrant responses to LPS and polyclonal stimulation by umbilical cord blood monocytes that were mediated by alterations in the epigenome. In this study, we show that pregravid obesity dysregulates umbilical cord blood monocyte responses to bacterial and viral pathogens. Specifically, interferon-stimulated gene expression and inflammatory responses to respiratory syncytial virus (RSV) and E. coli respectively were significantly dampened. Although upstream signaling events were comparable, translocation of the key transcription factor NF-kB and chromatin accessibility at pro-inflammatory gene promoters following TLR stimulation was significantly attenuated. Using a rhesus macaque model of western style diet-induced obesity, we further demonstrate that this defect is detected in fetal peripheral monocytes and tissue-resident macrophages during gestation. Collectively, these data indicate that maternal obesity alters metabolic, signaling, and epigenetic profiles of fetal monocytes leading to a state of immune paralysis during late gestation and at birth.

Hofbauer cells and fetal brain microglia share transcriptional profiles and responses to maternal diet-induced obesity

“…Specifically, the IPA analysis implicated activation of Fcψ-receptor mediated Phagocytosis in obesity-exposed microglia and HBC clusters, but suppression of Neuroinflammation Signaling Pathway (Fig 3E,F). This mixed picture of both macrophage activation and exhaustion in the setting of maternal immune activation is consistent with and extends published results, which describe not only fetal macrophage priming, activation and increased phagocytosis 22,23 in response to maternal obesity and other maternal immune-activating exposures, but also macrophage and monocyte exhaustion phenotypes 65,66 .…”

“…Our lab previously reported that obesity primed Mg and HBCs toward a pro-inflammatory phenotype when treated with LPS 23 . More recent studies show that macrophage and monocyte exhaustion plays a role in obesity-associated cellular programming 66 .…”

Western‐style diet in the presence of elevated circulating testosterone induces adipocyte hypertrophy without proinflammatory responses in rhesus macaques

“…LNs were collected into ice‐cold FACS buffer, diced with scalpels, mashed through a 70‐μm filter, and processed for cell isolation as described for WAT. Blood samples were collected in EDTA‐treated tubes and peripheral blood mononuclear cells (PBMCs) were isolated by centrifugation at 2000 rpm (800 × g ) for 30 min using a Lymphoprep gradient (STEMCELL Technologies) as described 21 …”

“…Blood samples were collected in EDTA-treated tubes and peripheral blood mononuclear cells (PBMCs) were isolated by centrifugation at 2000 rpm (800 × g) for 30 min using a Lymphoprep gradient (STEMCELL Technologies) as described. 21…”

“…For lymphoid staining, 5 × Functional responses in FBM and T12 macrophages were evaluated as described. 21 Specifically, 5 × 10 5 BM cells were stimulated with LPS (TLR4 agonist 1 μg/mL), Pam3CSK4 (TLR1/2 agonist, 1 μg/mL), or HKLM (TLR2 agonist, 10 8 particles/mL) for 8 h in the presence of 5 μg/mL brefeldin A (Sigma-Aldrich). TLR agonists were purchased from InvivoGen (San Diego, CA, USA).…”