Frontline Science: Endotoxin-induced immunotolerance is associated with loss of monocyte metabolic plasticity and reduction of oxidative burst
Frontline Science: Endotoxin-induced immunotolerance is associated with loss of monocyte metabolic plasticity and reduction of oxidative burst
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DOI：
10.1002/jlb.5hi0119-018r
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发表时间：
2019-07-01
影响因子：
5.5
通讯作者：
Gresnigt, Mark S.
中科院分区：
文献类型：
--
作者：
Grondman, Inge;Arts, Rob J. W.;Gresnigt, Mark S.
继发性感染是脓毒症的主要并发症，并与免疫状态受损相关，称为脓毒症诱导的免疫麻痹。引起免疫麻痹的分子机制尚不清楚;然而，白细胞细胞代谢的变化与免疫麻痹有关。我们研究了内毒素诱导的免疫耐受中代谢变化与抗微生物单核细胞功能的关系，作为脓毒症诱导的免疫麻痹的模型。在本研究中，通过静脉内毒素（2 ng/kg，来源于大肠杆菌O：113）给药在健康男性中诱导免疫耐受。在诱导免疫耐受之前和之后，分离循环中的CD 14（+）单核细胞并评估其抗菌功能，包括细胞因子产生、氧化爆发和微生物（白色念珠菌）杀灭能力，以及对离体刺激的代谢反应。接下来，在体外验证了细胞代谢改变对单核细胞功能的影响。离体脂多糖刺激诱导幼稚单核细胞代谢广泛的重新布线。相反，内毒素诱导的免疫耐受单核细胞没有表现出代谢可塑性，因为它们不能适应它们的代谢或安装细胞因子和氧化反应。验证实验表明，受免疫耐受影响的代谢途径的调节影响单核细胞细胞因子的产生、氧化爆发和微生物（C。白色念珠菌）杀死幼稚单核细胞。总的来说，这些数据表明，免疫耐受性单核细胞的特征在于代谢可塑性的丧失，这些代谢缺陷影响抗微生物单核细胞免疫功能。此外，这些发现支持免疫耐受单核细胞的细胞代谢改变可能揭示逆转脓毒症诱导的免疫麻痹的新的治疗靶点。
Secondary infections are a major complication of sepsis and associated with a compromised immune state, called sepsis-induced immunoparalysis. Molecular mechanisms causing immunoparalysis remain unclear; however, changes in cellular metabolism of leukocytes have been linked to immunoparalysis. We investigated the relation of metabolic changes to antimicrobial monocyte functions in endotoxin-induced immunotolerance, as a model for sepsis-induced immunoparalysis. In this study, immunotolerance was induced in healthy males by intravenous endotoxin (2 ng/kg, derived from Escherichia coli O:113) administration. Before and after induction of immunotolerance, circulating CD14(+) monocytes were isolated and assessed for antimicrobial functions, including cytokine production, oxidative burst, and microbial (Candida albicans) killing capacity, as well metabolic responses to ex vivo stimulation. Next, the effects of altered cellular metabolism on monocyte functions were validated in vitro. Ex vivo lipopolysaccharide stimulation induced an extensive rewiring of metabolism in naive monocytes. In contrast, endotoxin-induced immunotolerant monocytes showed no metabolic plasticity, as they were unable to adapt their metabolism or mount cytokine and oxidative responses. Validation experiments showed that modulation of metabolic pathways, affected by immunotolerance, influenced monocyte cytokine production, oxidative burst, and microbial (C. albicans) killing in naive monocytes. Collectively, these data demonstrate that immunotolerant monocytes are characterized by a loss of metabolic plasticity and these metabolic defects impact antimicrobial monocyte immune functions. Further, these findings support that the changed cellular metabolism of immunotolerant monocytes might reveal novel therapeutic targets to reverse sepsis-induced immunoparalysis.