Maternal obesity blunts antimicrobial responses in fetal monocytes.
Maternal obesity blunts antimicrobial responses in fetal monocytes.
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孕产妇肥胖会在胎儿单核细胞中钝化抗菌反应。
DOI：
10.7554/elife.81320
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发表时间：
2023-01-16
期刊：
影响因子：
7.7
通讯作者：
Messaoudi, Ilhem
中科院分区：
文献类型：
--
作者：
Sureshchandra, Suhas;Doratt, Brianna M.;Mendza, Norma;Varlamov, Oleg;Rincon, Monica;Marshall, Nicole E.;Messaoudi, Ilhem
母亲孕前(孕前)肥胖与母亲和子女的不良后果有关。在后代的并发症中，新生儿感染的易感性和严重性增加，需要进入重症监护病房，特别是细菌性败血症和小肠结肠炎。以前的研究已经报道了由表观基因组改变介导的脐血单核细胞对内毒素和多克隆刺激的异常反应。在这项研究中，我们发现孕前肥胖导致脐血单核细胞对细菌和病毒病原体的反应失调。具体地说，干扰素刺激的基因表达和对呼吸道合胞病毒(RSV)和大肠杆菌的炎症反应分别显著抑制。尽管上游信号事件具有可比性，但关键转录因子NF-κB的易位和促炎基因启动子上染色质的可及性在刺激后显著减弱。使用西式饮食诱导肥胖的恒河猴模型，我们进一步证明在妊娠期间胎儿外周血单核细胞和组织驻留巨噬细胞中检测到这种缺陷。总而言之，这些数据表明，母亲肥胖改变了胎儿单核细胞的代谢、信号和表观遗传学特征，导致了妊娠晚期和出生时的免疫瘫痪状态。
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 were significantly dampened, respectively . Although upstream signaling events were comparable, translocation of the key transcription factor NF-κB 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.