Immune effects of PI3K/Akt/HIF-1α-regulated glycolysis in polymorphonuclear neutrophils during sepsis.
Immune effects of PI3K/Akt/HIF-1α-regulated glycolysis in polymorphonuclear neutrophils during sepsis.
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败血症期间 PI3K/Akt/HIF-1α 调节多形核中性粒细胞糖酵解的免疫作用
DOI：
10.1186/s13054-022-03893-6
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发表时间：
2022-01-28
期刊：
影响因子：
--
通讯作者：
Qu H
中科院分区：
文献类型：
--
作者：
Pan T;Sun S;Chen Y;Tian R;Chen E;Tan R;Wang X;Liu Z;Liu J;Qu H
背景有效清除病原菌是改善脓毒症预后的关键。中性粒细胞(PMN)是天然细胞免疫的重要组成部分，在清除病原菌方面发挥着重要作用。然而，脓毒症时中性粒细胞的代谢特征和免疫调节途径尚未被研究。方法对14例败血症患者、26例急性阑尾炎患者和19例健康志愿者的中性粒细胞进行代谢组学分析。对健康志愿者和脓毒症患者分离的中性粒细胞进行转录组分析，评价其糖酵解情况，并探讨其作用机制。用脂多糖(LPS)刺激不同时间段健康志愿者分离的中性粒细胞，建立耐受模型。结果转录组在脓毒症过程中糖酵解和mTOR/HIF-1α信号通路发生明显变化。代谢组学显示，脓毒症患者的Warburg效应发生了显著改变。我们发现，在脓毒症过程中，糖酵解调节中性粒细胞的趋化和吞噬功能。乳酸脱氢酶A(LDHA)的下调是抑制PMN糖酵解的关键因素。本研究证实PI3K/Akt-HIF-1α通路参与了中性粒细胞低密度脂蛋白A的表达水平，并影响了中性粒细胞的趋化和吞噬功能。结论糖酵解抑制参与了脓毒症时中性粒细胞免疫抑制，并可能通过PI3K/AKT-HIF-1α通路下调中性粒细胞低密度脂蛋白的表达。本研究为脓毒症患者的管理和治疗提供了科学的理论依据，为寻找改善脓毒症患者免疫功能的治疗靶点提供了参考。
BackgroundEffective removal of pathogenic bacteria is key to improving the prognosis of sepsis. Polymorphonuclear neutrophils (PMNs) are the most important components of innate cellular immunity and play vital roles in clearing pathogenic bacteria. However, the metabolic characteristics and immunomodulatory pathways of PMNs during sepsis have not been investigated. In the present study, we explored the immune metabolism characteristics of PMNs and the mechanism by which neutrophilic glycolysis is regulated during sepsis.MethodsMetabolomics analysis was performed on PMNs isolated from 14 septic patients, 26 patients with acute appendicitis, and 19 healthy volunteers. Transcriptome analysis was performed on the PMNs isolated from the healthy volunteers and the patients with sepsis to assess glycolysis and investigate its mechanism. Lipopolysaccharide (LPS) was used to stimulate the neutrophils isolated from the healthy volunteers at different time intervals to build an LPS-tolerant model. Chemotaxis, phagocytosis, lactate production, oxygen consumption rate (OCR), and extracellular acidification rate (ECAR) were evaluated.ResultsTranscriptomics showed significant changes in glycolysis and the mTOR/HIF-1α signaling pathway during sepsis. Metabolomics revealed that the Warburg effect was significantly altered in the patients with sepsis. We discovered that glycolysis regulated PMNs’ chemotaxis and phagocytosis functions during sepsis. Lactate dehydrogenase A (LDHA) downregulation was a key factor in the inhibition of glycolysis in PMNs. This study confirmed that the PI3K/Akt-HIF-1α pathway was involved in the LDHA expression level and also influenced PMNs’ chemotaxis and phagocytosis functions.ConclusionsThe inhibition of glycolysis contributed to neutrophil immunosuppression during sepsis and might be controlled by PI3K/Akt-HIF-1α pathway-mediated LDHA downregulation. Our study provides a scientific theoretical basis for the management and treatment of patients with sepsis and promotes to identify therapeutic target for the improvement of immune function in sepsis.
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影响因子：
3.4
作者：
Beck H;Jeske M;Thede K;Stoll F;Flamme I;Akbaba M;Ergüden JK;Karig G;Keldenich J;Oehme F;Militzer HC;Hartung IV;Thuss U
通讯作者：
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影响因子：
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作者：
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通讯作者：
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作者：
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DOI：
10.1186/s13046-019-1351-4
发表时间：
2019-08-27
影响因子：
11.3
作者：
Jin, Jinmei;Qiu, Shuiping;Wu, Xiaojun
通讯作者：
Wu, Xiaojun
影响因子：
4
作者：
Ellinghaus, Peter;Heisler, Iring;Unterschemmann, Kerstin;Haerter, Michael;Beck, Hartmut;Greschat, Susanne;Ehrmann, Alexander;Summer, Holger;Flamme, Ingo;Oehme, Felix;Thierauch, Karlheinz;Michels, Martin;Hess-Stumpp, Holger;Ziegelbauer, Karl
通讯作者：
Ziegelbauer, Karl