The Cytokine Response to Lipopolysaccharide Does Not Predict the Host Response to Infection.
The Cytokine Response to Lipopolysaccharide Does Not Predict the Host Response to Infection.
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DOI：
10.4049/jimmunol.1602106
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发表时间：
2017-04-15
期刊：
影响因子：
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通讯作者：
Bohannon JK
中科院分区：
文献类型：
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作者：
Fensterheim BA;Guo Y;Sherwood ER;Bohannon JK
脂多糖（LPS）引起的细胞因子反应的幅度通常用于评估危重患者的免疫功能。被抑制的反应（称为内毒素耐受性）与更差的结果相关，但已知诱导内毒素耐受性的Toll样受体4（TLR 4）配体可以保护动物免受感染。因此，它仍然是未知的LPS引起的细胞因子反应的幅度是否提供了一个准确的评估抗菌免疫力。为了解决这个问题，评估了不同TLR配体修饰LPS引起的细胞因子应答和对感染的抗性的能力。用LPS、单磷酰脂质A（MPLA）或poly（I：C）引发的小鼠显著降低血浆LPS引起的促炎细胞因子，反映内毒素耐受性，而CpG-ODN引发的小鼠显示增加的细胞因子产生。相比之下，LPS、MPLA和CpG-ODN，而不是poly（I：C），改善了宿主对铜绿假单胞菌感染的应答。值得注意的是，用保护性TLR配体（包括CpG-ODN）致敏的小鼠在铜绿假单胞菌感染期间显示出降低的血浆细胞因子。TLR配体给予的保护持续长达15天，但不依赖于适应性免疫系统。在骨髓源性巨噬细胞中，保护性TLR配体诱导了一种持久的代谢表型，其特征在于糖酵解和氧化代谢升高以及大小、粒度、吞噬作用和呼吸爆发增加。TLR引发细胞糖酵解的持续增强部分依赖于缺氧诱导因子1-α，并且对于增加吞噬作用至关重要。总之，LPS诱导的细胞因子产生的幅度并不指示暴露于TLR配体后的抗微生物免疫。保护性TLR配体诱导吞噬细胞代谢和抗微生物功能的持续增强。
The magnitude of the lipopolysaccharide (LPS)-elicited cytokine response is commonly used to assess immune function in critically ill patients. A suppressed response, known as endotoxin tolerance, is associated with worse outcomes, yet endotoxin tolerance-inducing toll-like receptor 4 (TLR4) ligands are known to protect animals from infection. Thus, it remains unknown whether the magnitude of the LPS-elicited cytokine response provides an accurate assessment of antimicrobial immunity. To address this question, the ability of diverse TLR ligands to modify the LPS-elicited cytokine response and resistance to infection were assessed. Priming of mice with LPS, monophosphoryl lipid A (MPLA), or poly(I:C) significantly reduced plasma LPS-elicited pro-inflammatory cytokines, reflecting endotoxin tolerance, whereas CpG-ODN-primed mice showed augmented cytokine production. In contrast, LPS, MPLA, and CpG-ODN, but not poly(I:C), improved the host response to a P. aeruginosa infection. Notably, mice primed with protective TLR ligands, including CpG-ODN, showed reduced plasma cytokines during P. aeruginosa infection. The protection imparted by TLR ligands persisted for up to 15 days yet was independent of the adaptive immune system. In bone marrow-derived macrophages, protective TLR ligands induced a persistent metabolic phenotype characterized by elevated glycolysis and oxidative metabolism as well as augmented size, granularity, phagocytosis, and respiratory burst. Sustained augmentation of glycolysis in TLR-primed cells was dependent, in part, on hypoxia-inducible factor 1-alpha and was essential for increased phagocytosis. In conclusion, the magnitude of LPS-elicited cytokine production is not indicative of antimicrobial immunity after exposure to TLR ligands. Protective TLR ligands induce sustained augmentation of phagocyte metabolism and antimicrobial function.