Lactic Acid Inhibits Lipopolysaccharide-Induced Mast Cell Function by Limiting Glycolysis and ATP Availability
Lactic Acid Inhibits Lipopolysaccharide-Induced Mast Cell Function by Limiting Glycolysis and ATP Availability
复制标题
乳酸通过限制糖酵解和三磷酸腺苷（ATP）的生成，抑制脂多糖诱导的肥大细胞功能 。
DOI：
10.4049/jimmunol.1801005
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发表时间：
2019-07-15
影响因子：
4.4
通讯作者：
Ryan, John J.
中科院分区：
文献类型：
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作者：
Caslin, Heather L.;Abebayehu, Daniel;Ryan, John J.
脓毒症有一个被充分研究的炎症期，还有一个鲜为人知的继发免疫抑制期。血乳酸升高和乳酸清除缓慢与死亡率相关；然而，调控作用尚不清楚。我们假设乳酸（LA）有助于晚期，而不仅仅是细菌感染的结果。目前还没有研究证实LA在体内脓毒症模型中的作用，也没有研究证实其在体外抑制lps诱导的激活的机制。由于肥大细胞可以被全身激活并导致败血症，我们研究了LA对肥大细胞对LPS反应的影响。LA显著抑制lps诱导的小鼠骨髓源性肥大细胞的细胞因子产生和NF-kappa B转录活性以及腹膜肥大细胞的细胞因子产生。抑制作用依赖于MCT-1，乳酸钠或甲酸可重复抑制。此外，LA显著抑制lps诱导小鼠内毒素血症后的细胞因子诱导。由于糖酵解与炎症有关，而LA是这一过程的副产品，因此我们研究了葡萄糖代谢的变化。在LPS刺激下，LA处理降低了葡萄糖摄取和乳酸输出。糖酵解抑制剂可以模拟LA的作用，并通过增加ATP的可用性来逆转。这些结果表明糖酵解抑制和ATP的产生是LA效应的必要和充分条件。我们的研究表明，增强糖酵解和ATP的产生可以改善免疫功能，在脓毒症的免疫抑制阶段抵消LA的抑制作用。
Sepsis has a well-studied inflammatory phase, with a less-understood secondary immunosuppressive phase. Elevated blood lactate and slow lactate clearance are associated with mortality; however, regulatory roles are unknown. We hypothesized that lactic acid (LA) contributes to the late phase and is not solely a consequence of bacterial infection. No studies have examined LA effects in sepsis models in vivo or a mechanism by which it suppresses LPS-induced activation in vitro. Because mast cells can be activated systemically and contribute to sepsis, we examined LA effects on the mast cell response to LPS. LA significantly suppressed LPS-induced cytokine production and NF-kappa B transcriptional activity in mouse bone marrow-derived mast cells and cytokine production in peritoneal mast cells. Suppression was MCT-1 dependent and reproducible with sodium lactate or formic acid. Further, LA significantly suppressed cytokine induction following LPS-induced endotoxemia in mice. Because glycolysis is linked to inflammation and LA is a byproduct of this process, we examined changes in glucose metabolism. LA treatment reduced glucose uptake and lactate export during LPS stimulation. LA effects were mimicked by glycolytic inhibitors and reversed by increasing ATP availability. These results indicate that glycolytic suppression and ATP production are necessary and sufficient for LA effects. Our work suggests that enhancing glycolysis and ATP production could improve immune function, counteracting LA suppressive effects in the immunosuppressive phase of sepsis.