Sepsis is associated with a strong inflammatory reaction triggering a complex and prolonged immune response. Septic patients have been shown to develop sustained immunosuppression due to a reduced responsiveness of leukocytes to pathogens. Changes in cellular metabolism of leukocytes have been linked to this phenomenon and contribute to the ongoing immunological derangement. However, the underlying mechanisms of these phenomena are incompletely understood. In cell culture models, we mimicked LPS tolerance conditions to provide evidence that epigenetic modifications account for monocyte metabolic changes which cause immune paralysis in restimulated septic monocytes. In detail, we observed differential methylation of CpG sites related to metabolic activity in human PBMCs 18 h after septic challenge. The examination of changes in immune function and metabolic pathways was performed in LPS-tolerized monocytic THP-1 cells. Passaged THP-1 cells, inheriting initial LPS challenge, presented with dysregulation of cytokine expression and oxygen consumption for up to 7 days after the initial LPS treatment. Proinflammatory cytokine concentrations of TNFα and IL1β were significantly suppressed following a second LPS challenge () on day 7 after first LPS stimulation. However, the analysis of cellular metabolism did not reveal any noteworthy alterations between tolerant and nontolerant THP-1 monocytes. No quantitative differences in ATP and NADH synthesis or participating enzymes of energy metabolism occurred. Our data demonstrate that the function and epigenetic modifications of septic and tolerized monocytes can be examined in vitro with the help of our LPS model. Changes in CpG site methylation and monocyte function point to a correlation between epigenetic modification in metabolic pathways and reduced monocyte function under postseptic conditions.

中文翻译：

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内毒素耐受的单核细胞持续免疫麻痹。

脓毒症与强烈的炎症反应相关，触发复杂而长时间的免疫反应。已经证实败血症患者由于白细胞对病原体的应答性降低而产生持续的免疫抑制。白细胞的细胞代谢变化与这种现象有关，并导致正在进行的免疫紊乱。但是，这些现象的潜在机制尚未完全理解。在细胞培养模型中，我们模拟了LPS耐受条件，以提供表观遗传修饰说明单核细胞代谢变化的证据，这些变化会导致再刺激的败血性单核细胞免疫麻痹。详细地，我们观察到败血性攻毒后18 h，人PBMC中与代谢活性相关的CpG位点甲基化差异。免疫功能和代谢途径的变化的检查是在LPS耐受的单核THP-1细胞中进行的。传代的THP-1细胞继承了最初的LPS攻击，在最初的LPS治疗后长达7天呈现出细胞因子表达失调和耗氧量。TNF的炎性细胞因子浓度α和IL- β均显著抑制之后的第二LPS攻击（）在第一次LPS刺激后的第7天。但是，细胞代谢分析并未显示出耐受性和非耐受性THP-1单核细胞之间的任何显着变化。ATP和NADH合成或能量代谢参与酶未发生定量差异。我们的数据表明败血病和耐受的单核细胞的功能和表观遗传修饰可以在我们的LPS模型的帮助下进行体外检查。CpG位点甲基化和单核细胞功能的变化表明，在代谢条件下，代谢途径中的表观遗传修饰与单核细胞功能降低之间存在相关性。