Mitochondrial Sirtuin 4 Resolves Immune Tolerance in Monocytes by Rebalancing Glycolysis and Glucose Oxidation Homeostasis.
Mitochondrial Sirtuin 4 Resolves Immune Tolerance in Monocytes by Rebalancing Glycolysis and Glucose Oxidation Homeostasis.
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DOI：
10.3389/fimmu.2018.00419
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发表时间：
2018
影响因子：
7.3
通讯作者：
Liu TF
中科院分区：
文献类型：
--
作者：
Tao J;Zhang J;Ling Y;McCall CE;Liu TF
本研究的目的是确定免疫耐受生理转化为急性炎症反应消退的分子机制，这是未知的。这种知识差距及其临床重要性的一个例子是来自人类和小鼠脓毒症非幸存者的血液单核细胞中广泛的能量缺乏和免疫代谢瘫痪，这妨碍了脓毒症的解决。这种免疫代谢失调被糖酵解和TNF-α表达增加的离体内毒素耐受性所破坏。为了研究耐受性如何转变为消退，我们将先前记录的与诱导内毒素耐受性的急性炎症、免疫和代谢重编程相关的模型改编为人单核细胞脓毒症模型。我们在这里报告，线粒体sirtuin 4（SIRT 4）生理上打破耐受性，并解决急性炎症的人单核细胞通过协调重新编程的代谢和生物能量学。我们发现，在免疫耐受过程中SIRT 4 mRNA和蛋白表达的增加抵消了丙酮酸脱氢酶激酶1（PDK 1）和SIRT 1的增加，通过将葡萄糖依赖性免疫耐受支持转换为脂肪酸氧化支持免疫耐受来促进耐受。通过减少PDK 1，丙酮酸脱氢酶复合物重新激活重新平衡线粒体呼吸，并通过减少SIRT 1，SIRT 4抑制脂肪酸氧化。线粒体SIRT 4核反馈的精确机制尚不清楚。我们的研究结果与线粒体SIRT 4指导控制合成代谢和分解代谢能量来源的轴的新概念一致。
The goal of this investigation was to define the molecular mechanism underlying physiologic conversion of immune tolerance to resolution of the acute inflammatory response, which is unknown. An example of this knowledge gap and its clinical importance is the broad-based energy deficit and immunometabolic paralysis in blood monocytes from non-survivors of human and mouse sepsis that precludes sepsis resolution. This immunometabolic dysregulation is biomarked by ex vivo endotoxin tolerance to increased glycolysis and TNF-α expression. To investigate how tolerance switches to resolution, we adapted our previously documented models associated with acute inflammatory, immune, and metabolic reprogramming that induces endotoxin tolerance as a model of sepsis in human monocytes. We report here that mitochondrial sirtuin 4 (SIRT4) physiologically breaks tolerance and resolves acute inflammation in human monocytes by coordinately reprogramming of metabolism and bioenergetics. We find that increased SIRT4 mRNA and protein expression during immune tolerance counters the increase in pyruvate dehydrogenase kinase 1 (PDK1) and SIRT1 that promote tolerance by switching glucose-dependent support of immune resistance to fatty acid oxidation support of immune tolerance. By decreasing PDK1, pyruvate dehydrogenase complex reactivation rebalances mitochondrial respiration, and by decreasing SIRT1, SIRT4 represses fatty acid oxidation. The precise mechanism for the mitochondrial SIRT4 nuclear feedback is unclear. Our findings are consistent with a new concept in which mitochondrial SIRT4 directs the axis that controls anabolic and catabolic energy sources.