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TNF-Signaling Modulates Neutrophil-Mediated Immunity at the Feto-Maternal Interface During LPS-Induced Intrauterine Inflammation.
Frontiers in Immunology ( IF 5.7 ) Pub Date : 2020-04-03 , DOI: 10.3389/fimmu.2020.00558
Pietro Presicce 1 , Monica Cappelletti 1 , Paranthaman Senthamaraikannan 2 , Feiyang Ma 3 , Marco Morselli 3, 4 , Courtney M Jackson 5 , Shibabrata Mukherjee 5 , Lisa A Miller 6, 7 , Matteo Pellegrini 3, 4 , Alan H Jobe 2 , Claire A Chougnet 5 , Suhas G Kallapur 1
Affiliation  

Accumulation of activated neutrophils at the feto-maternal interface is a defining hallmark of intrauterine inflammation (IUI) that might trigger an excessive immune response during pregnancy. Mechanisms responsible of this massive neutrophil recruitment are poorly investigated. We have previously showed that intraamniotic injection of LPS in rhesus macaques induced a neutrophil predominant inflammatory response similar to that seen in human IUI. Here, we demonstrate that anti-TNF antibody (Adalimumab) inhibited ~80% of genes induced by LPS involved in inflammatory signaling and innate immunity in chorio-decidua neutrophils. Consistent with the gene expression data, TNF-blockade decreased LPS-induced neutrophil accumulation and activation at the feto-maternal interface. We also observed a reduction in IL-6 and other pro-inflammatory cytokines but not prostaglandins concentrations in the amniotic fluid. Moreover, TNF-blockade decreased mRNA expression of inflammatory cytokines in the chorio-decidua but not in the uterus, suggesting that inhibition of TNF-signaling decreased the inflammation in a tissue-specific manner within the uterine compartment. Taken together, our results demonstrate a predominant role for TNF-signaling in modulating the neutrophilic infiltration at the feto-maternal interface during IUI and suggest that blockade of TNF-signaling could be considered as a therapeutic approach for IUI, the major leading cause of preterm birth.

中文翻译:

在 LPS 诱导的宫内炎症期间,TNF 信号调节胎儿-母体界面的中性粒细胞介导的免疫。

激活的中性粒细胞在胎儿-母体界面的积累是宫内炎症 (IUI) 的一个决定性标志,它可能会在怀孕期间引发过度的免疫反应。导致这种大规模中性粒细胞募集的机制研究得很少。我们之前已经表明,在恒河猴中羊膜内注射 LPS 会诱导以中性粒细胞为主的炎症反应,类似于人类 IUI。在这里,我们证明了抗 TNF 抗体(阿达木单抗)抑制了约 80% 的由 LPS 诱导的基因,这些基因涉及绒毛膜蜕膜中性粒细胞的炎症信号传导和先天免疫。与基因表达数据一致,TNF 阻断减少了 LPS 诱导的中性粒细胞在胎儿-母体界面的积累和激活。我们还观察到羊水中 IL-6 和其他促炎细胞因子的浓度降低,但前列腺素的浓度没有降低。此外,TNF 阻断降低了绒毛膜蜕膜中炎性细胞因子的 mRNA 表达,但不在子宫中,表明 TNF 信号传导的抑制以组织特异性方式减少了子宫隔室内的炎症。总之,我们的结果表明 TNF 信号在调节 IUI 期间胎儿-母体界面处的中性粒细胞浸润中起主要作用,并表明阻断 TNF 信号可被视为 IUI 的治疗方法,IUI 是早产的主要原因出生。TNF 阻断降低了绒毛膜蜕膜中炎性细胞因子的 mRNA 表达,但不在子宫中,这表明 TNF 信号传导的抑制以组织特异性方式减少了子宫隔室中的炎症。总之,我们的结果表明 TNF 信号在调节 IUI 期间胎儿-母体界面处的中性粒细胞浸润中起主要作用,并表明阻断 TNF 信号可被视为 IUI 的治疗方法,IUI 是早产的主要原因出生。TNF 阻断降低了绒毛膜蜕膜中炎性细胞因子的 mRNA 表达,但不在子宫中,这表明 TNF 信号传导的抑制以组织特异性方式减少了子宫隔室中的炎症。总之,我们的结果表明 TNF 信号在调节 IUI 期间胎儿-母体界面处的中性粒细胞浸润中起主要作用,并表明阻断 TNF 信号可被视为 IUI 的治疗方法,IUI 是早产的主要原因出生。
更新日期:2020-04-06
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