PDF(Pubmed)
Abstract：
BACKGROUND: Preterm birth preceded by spontaneous preterm labour often occurs in the clinical setting of sterile intra-amniotic inflammation (SIAI), a condition that currently lacks treatment.
METHODS: Proteomic and scRNA-seq human data were analysed to evaluate the role of IL-6 and IL-1α in SIAI. A C57BL/6 murine model of SIAI-induced preterm birth was developed by the ultrasound-guided intra-amniotic injection of IL-1α. The blockade of IL-6R by using an aIL-6R was tested as prenatal treatment for preterm birth and adverse neonatal outcomes. QUEST-MRI evaluated brain oxidative stress in utero. Targeted transcriptomic profiling assessed maternal, foetal, and neonatal inflammation. Neonatal biometrics and neurodevelopment were tested. The neonatal gut immune-microbiome was evaluated using metagenomic sequencing and immunophenotyping.
RESULTS: IL-6 plays a critical role in the human intra-amniotic inflammatory response, which is associated with elevated concentrations of the alarmin IL-1α. Intra-amniotic injection of IL-1α resembles SIAI, inducing preterm birth (7% vs. 50%, p = 0.03, Fisher\'s exact test) and neonatal mortality (18% vs. 56%, p = 0.02, Mann-Whitney U-test). QUEST-MRI revealed no foetal brain oxidative stress upon in utero IL-1α exposure (p > 0.05, mixed linear model). Prenatal treatment with aIL-6R abrogated IL-1α-induced preterm birth (50% vs. 7%, p = 0.03, Fisher\'s exact test) by dampening inflammatory processes associated with the common pathway of labour. Importantly, aIL-6R reduces neonatal mortality (56% vs. 22%, p = 0.03, Mann-Whitney U-test) by crossing from the mother to the amniotic cavity, dampening foetal organ inflammation and improving growth. Beneficial effects of prenatal IL-6R blockade carried over to neonatal life, improving survival, growth, neurodevelopment, and gut immune homeostasis.
CONCLUSIONS: IL-6R blockade can serve as a strategy to treat SIAI, preventing preterm birth and adverse neonatal outcomes.
BACKGROUND: NICHD/NIH/DHHS, Contract HHSN275201300006C. WSU Perinatal Initiative in Maternal, Perinatal and Child Health.
METHODS: Proteomic and scRNA-seq human data were analysed to evaluate the role of IL-6 and IL-1α in SIAI. A C57BL/6 murine model of SIAI-induced preterm birth was developed by the ultrasound-guided intra-amniotic injection of IL-1α. The blockade of IL-6R by using an aIL-6R was tested as prenatal treatment for preterm birth and adverse neonatal outcomes. QUEST-MRI evaluated brain oxidative stress in utero. Targeted transcriptomic profiling assessed maternal, foetal, and neonatal inflammation. Neonatal biometrics and neurodevelopment were tested. The neonatal gut immune-microbiome was evaluated using metagenomic sequencing and immunophenotyping.
RESULTS: IL-6 plays a critical role in the human intra-amniotic inflammatory response, which is associated with elevated concentrations of the alarmin IL-1α. Intra-amniotic injection of IL-1α resembles SIAI, inducing preterm birth (7% vs. 50%, p = 0.03, Fisher\'s exact test) and neonatal mortality (18% vs. 56%, p = 0.02, Mann-Whitney U-test). QUEST-MRI revealed no foetal brain oxidative stress upon in utero IL-1α exposure (p > 0.05, mixed linear model). Prenatal treatment with aIL-6R abrogated IL-1α-induced preterm birth (50% vs. 7%, p = 0.03, Fisher\'s exact test) by dampening inflammatory processes associated with the common pathway of labour. Importantly, aIL-6R reduces neonatal mortality (56% vs. 22%, p = 0.03, Mann-Whitney U-test) by crossing from the mother to the amniotic cavity, dampening foetal organ inflammation and improving growth. Beneficial effects of prenatal IL-6R blockade carried over to neonatal life, improving survival, growth, neurodevelopment, and gut immune homeostasis.
CONCLUSIONS: IL-6R blockade can serve as a strategy to treat SIAI, preventing preterm birth and adverse neonatal outcomes.
BACKGROUND: NICHD/NIH/DHHS, Contract HHSN275201300006C. WSU Perinatal Initiative in Maternal, Perinatal and Child Health.
摘要：
背景：在无菌羊膜腔内炎症（SIAI）的临床环境中，通常会发生自发早产的早产，目前缺乏治疗的情况。
方法：分析了蛋白质组学和scRNA-seq人类数据，以评估IL-6和IL-1α在SIAI中的作用。通过超声引导羊膜腔内注射IL-1α，建立了SIAI诱导的C57BL/6小鼠早产模型。使用aIL-6R阻断IL-6R作为早产和不良新生儿结局的产前治疗进行了测试。QUEST-MRI评估子宫内脑氧化应激。靶向转录组分析评估了母体，胎儿,和新生儿炎症。对新生儿生物特征和神经发育进行了测试。使用宏基因组测序和免疫表型对新生儿肠道免疫微生物组进行评估。
结果：IL-6在人羊膜腔内炎症反应中起关键作用，这与alarminIL-1α的浓度升高有关。羊膜腔内注射IL-1α类似于SIAI，诱导早产(7%vs.50%,p=0.03，Fisher精确检验)和新生儿死亡率(18%与56%,p=0.02，曼-惠特尼U检验)。QUEST-MRI显示子宫内IL-1α暴露时没有胎儿脑氧化应激(p>0.05,混合线性模型)。用aIL-6R进行的产前治疗废除了IL-1α诱导的早产（50％vs.7%,p=0.03，Fisher精确检验）通过抑制与常见分娩途径相关的炎症过程。重要的是,aIL-6R降低新生儿死亡率(56%vs.22%,p=0.03，Mann-WhitneyU检验）从母亲穿过羊膜腔，抑制胎儿器官炎症和促进生长。产前IL-6R阻断对新生儿生命的有益影响，改善生存,增长,神经发育，和肠道免疫稳态。
结论：IL-6R阻断可以作为治疗SIAI的策略，预防早产和不良新生儿结局。
背景：NICHD/NIH/DHHS，合同HHSN275201300006C。WSU围产期倡议，围产期和儿童健康。
方法：分析了蛋白质组学和scRNA-seq人类数据，以评估IL-6和IL-1α在SIAI中的作用。通过超声引导羊膜腔内注射IL-1α，建立了SIAI诱导的C57BL/6小鼠早产模型。使用aIL-6R阻断IL-6R作为早产和不良新生儿结局的产前治疗进行了测试。QUEST-MRI评估子宫内脑氧化应激。靶向转录组分析评估了母体，胎儿,和新生儿炎症。对新生儿生物特征和神经发育进行了测试。使用宏基因组测序和免疫表型对新生儿肠道免疫微生物组进行评估。
结果：IL-6在人羊膜腔内炎症反应中起关键作用，这与alarminIL-1α的浓度升高有关。羊膜腔内注射IL-1α类似于SIAI，诱导早产(7%vs.50%,p=0.03，Fisher精确检验)和新生儿死亡率(18%与56%,p=0.02，曼-惠特尼U检验)。QUEST-MRI显示子宫内IL-1α暴露时没有胎儿脑氧化应激(p>0.05,混合线性模型)。用aIL-6R进行的产前治疗废除了IL-1α诱导的早产（50％vs.7%,p=0.03，Fisher精确检验）通过抑制与常见分娩途径相关的炎症过程。重要的是,aIL-6R降低新生儿死亡率(56%vs.22%,p=0.03，Mann-WhitneyU检验）从母亲穿过羊膜腔，抑制胎儿器官炎症和促进生长。产前IL-6R阻断对新生儿生命的有益影响，改善生存,增长,神经发育，和肠道免疫稳态。
结论：IL-6R阻断可以作为治疗SIAI的策略，预防早产和不良新生儿结局。
背景：NICHD/NIH/DHHS，合同HHSN275201300006C。WSU围产期倡议，围产期和儿童健康。
