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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >The wild-derived inbred mouse strain SPRET/Ei is resistant to LPS and defective in IFN-β production
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The wild-derived inbred mouse strain SPRET/Ei is resistant to LPS and defective in IFN-β production

机译：野生来源的自交小鼠品系SPRET / Ei对LPS有抗性，并且在IFN-β产生方面存在缺陷

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Although activation of Toll-like receptor 4 (TLR4)-positive cells is essential for eliminating Gram-negative bacteria, overactivation of these cells by the TLR4 ligand LPS initiates a systemic inflammatory reaction and shock. Here we demonstrate that SPRET/Ei mice, derived from Mus spretus, exhibit a dominant resistance against LPS-induced lethality. This resistance is mediated by bone marrow-derived cells. Macrophages from these mice exhibit normal signaling and gene expression responses that depend on the myeloid differentiation factor 88 adaptor protein, but they are impaired in IFN-β production. The defect appears to be specific for IFN-β, although the SPRET/Ei IFN-β promoter is normal. In vivo IFN-β induction by LPS or influenza virus is very low in SPRET/Ei mice, but IFN-β-treatment restores the sensitivity to LPS, and IFN type 1 receptor-deficient mice are also resistant to LPS. Because of the defective induction of IFN-β, these mice are completely resistant to Listeria monocytogenes and highly sensitive to Leishmania major infection. Stimulation of SPRET/Ei macrophages leads to rapid down-regulation of IFN type 1 receptor mRNA expression, which is reflected in poor induction of IFN-β-dependent genes. This finding indicates that the resistance of SPRET/Ei mice to LPS is due to disruption of a positive-feedback loop that amplifies IFN-β production. In contrast to TLR4-deficient mice, SPRET/Ei mice resist both LPS and sepsis induced with Klebsiella pneumoniae.
机译：尽管Toll样受体4（TLR4）阳性细胞的激活对于消除革兰氏阴性细菌至关重要，但是TLR4配体LPS对这些细胞的过度激活会引发全身性炎症反应和休克。在这里，我们证明SPRES / Ei小鼠，衍生自穆斯普勒斯鼠（Mus spretus），表现出对LPS致死性的显性抗性。这种抗性是由骨髓来源的细胞介导的。这些小鼠的巨噬细胞显示出正常的信号传导和基因表达反应，这取决于髓样分化因子88衔接子蛋白，但它们的IFN-β产生受到损害。尽管SPRET / EiIFN-β启动子是正常的，但该缺陷似乎对IFN-β具有特异性。在SPRET / Ei小鼠中，LPS或流感病毒在体内对IFN-β的诱导非常低，但是IFN-β处理可恢复对LPS的敏感性，而IFN 1型受体缺陷型小鼠也对LPS耐药。由于IFN-β的诱导缺陷，因此这些小鼠对单核细胞增生性李斯特菌完全耐药，并且对利什曼原虫主要感染高度敏感。 SPRET / Ei巨噬细胞的刺激导致IFN 1型受体mRNA表达的快速下调，这反映在IFN-β依赖基因的诱导不良上。这一发现表明，SPRET / Ei小鼠对LPS的抗性是由于放大IFN-β产生的正反馈回路的破坏。与TLR4缺陷小鼠相反，SPRET / Ei小鼠抵抗肺炎克雷伯菌引起的LPS和败血症。

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