Viral Infection Sensitizes Human Fetal Membranes to Bacterial Lipopolysaccharide by MERTK Inhibition and Inflammasome Activation.
Viral Infection Sensitizes Human Fetal Membranes to Bacterial Lipopolysaccharide by MERTK Inhibition and Inflammasome Activation.
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DOI：
10.4049/jimmunol.1700870
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发表时间：
2017-10-15
期刊：
影响因子：
--
通讯作者：
Abrahams VM
中科院分区：
文献类型：
--
作者：
Cross SN;Potter JA;Aldo P;Kwon JY;Pitruzzello M;Tong M;Guller S;Rothlin CV;Mor G;Abrahams VM
绒毛膜炎、胎膜早破（FM）和随后的早产与局部感染和炎症，特别是白细胞介素1 β（IL-1β）的产生有关。虽然细菌感染是常见的，但其他微生物可能在发病机制中发挥作用。由于流感、埃博拉和寨卡等病毒大流行越来越普遍，孕妇患相关并发症的风险也越来越高，因此这项研究评估了病毒感染对人类FM先天免疫反应的影响。这项研究表明，FM的疱疹病毒感染使组织对低水平的细菌脂多糖（LPS）敏感，从而引起过度的IL-1β反应。使用离体人FM外植体系统和体内小鼠妊娠模型，我们报告了这种加重炎症的机制是通过抑制TAM受体、MERTK和激活炎性小体。TAM受体配体，生长停滞特异性6（GAS 6），通过恢复和增强TAM受体和配体表达，并防止IL-1β加工和分泌加剧，重建对LPS的正常FM反应。这些发现表明了一种新的机制，病毒通过这种机制改变了正常的FM对细菌的免疫反应，可能导致不良的妊娠结局。
Chorioamnionitis, premature rupture of fetal membranes (FM), and subsequent preterm birth are associated with local infection and inflammation, particularly interleukin 1 beta (IL-1β) production. While bacterial infections are commonly identified, other microorganisms may play a role in the pathogenesis. Since viral pandemics, such as influenza, Ebola and Zika are becoming more common, and pregnant women are at increased risk of associated complications, this study evaluated the impact viral infection had on human FM innate immune responses. This study shows that a herpes viral infection of FMs sensitizes the tissue to low levels of bacterial lipopolysaccharide (LPS), giving rise to an exaggerated IL-1β response. Using an ex vivo human FM explant system and an in vivo mouse model of pregnancy, we report that the mechanism by which this aggravated inflammation arises is through the inhibition of the TAM receptor, MERTK, and activation of the inflammasome. The TAM receptor ligand, growth arrest specific 6 (GAS6), re-establishes the normal FM response to LPS by restoring and augmenting TAM receptor and ligand expression, and by preventing the exacerbated IL-1β processing and secretion. These findings indicate a novel mechanism by which viruses alter normal FM immune responses to bacteria, potentially giving rise to adverse pregnancy outcomes.
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