Deficiency of Myeloid Pfkfb3 Protects Mice From Lung Edema and Cardiac Dysfunction in LPS-Induced Endotoxemia.
Deficiency of Myeloid Pfkfb3 Protects Mice From Lung Edema and Cardiac Dysfunction in LPS-Induced Endotoxemia.
复制标题
骨髓 Pfkfb3 缺乏可保护小鼠免受 LPS 诱导的内毒素血症中的肺水肿和心脏功能障碍
DOI：
10.3389/fcvm.2021.745810
复制
发表时间：
2021
影响因子：
3.6
通讯作者：
Huo Y
中科院分区：
文献类型：
--
作者：
Xu J;Wang L;Yang Q;Ma Q;Zhou Y;Cai Y;Mao X;Da Q;Lu T;Su Y;Bagi Z;Lucas R;Liu Z;Hong M;Ouyang K;Huo Y
脓毒症是一种由过度炎症反应导致多器官衰竭的病理学，是重症监护病房死亡的主要原因。巨噬细胞在脓毒症的病理生理中起重要作用。越来越多的证据表明，有氧糖酵解速率上调是活化的促炎性巨噬细胞的一个关键共同特征。在这里，我们确定了髓样6-磷酸果糖-2-激酶/果糖-2，6-二磷酸酶3（Pfkfb 3），在脂多糖（LPS）诱导的小鼠内毒素血症的糖酵解激活剂的关键作用。在体外用LPS处理的骨髓衍生的巨噬细胞（BMDM）中和在体内用LPS攻击的小鼠的肺巨噬细胞中，Pfkfb 3表达显著增加。Pfkfb 3的骨髓特异性敲除可保护小鼠免受LPS诱导的肺水肿、心功能不全和低血压，这与白细胞介素1 β（IL 1b）、白细胞介素6（IL 6）和一氧化氮合酶2（Nos 2）的表达减少以及肺组织中中性粒细胞和巨噬细胞浸润减少有关。在培养的巨噬细胞中Pfkfb 3消融减弱了LPS诱导的糖酵解通量，导致促炎基因表达减少。机制上，Pfkfb 3消融或用Pfkfb 3抑制剂AZ 26抑制通过NF-κB信号通路抑制LPS诱导的促炎基因表达。总之，我们的研究揭示了Pfkfb 3通过重编程巨噬细胞代谢和调节促炎基因表达在LPS诱导的脓毒症中的关键作用。因此，PFKFB 3是预防和治疗脓毒症等炎症性疾病的潜在靶点。
Sepsis, a pathology resulting from excessive inflammatory response that leads to multiple organ failure, is a major cause of mortality in intensive care units. Macrophages play an important role in the pathophysiology of sepsis. Accumulating evidence has suggested an upregulated rate of aerobic glycolysis as a key common feature of activated proinflammatory macrophages. Here, we identified a crucial role of myeloid 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (Pfkfb3), a glycolytic activator in lipopolysaccharide (LPS)-induced endotoxemia in mice. Pfkfb3 expression is substantially increased in bone marrow derived macrophages (BMDMs) treated with LPS in vitro and in lung macrophages of mice challenged with LPS in vivo. Myeloid-specific knockout of Pfkfb3 in mice protects against LPS-induced lung edema, cardiac dysfunction and hypotension, which were associated with decreased expression of interleukin 1 beta (Il1b), interleukin 6 (Il6) and nitric oxide synthase 2 (Nos2), as well as reduced infiltration of neutrophils and macrophages in lung tissue. Pfkfb3 ablation in cultured macrophages attenuated LPS-induced glycolytic flux, resulting in a decrease in proinflammatory gene expression. Mechanistically, Pfkfb3 ablation or inhibition with a Pfkfb3 inhibitor AZ26 suppresses LPS-induced proinflammatory gene expression via the NF-κB signaling pathway. In summary, our study reveals the critical role of Pfkfb3 in LPS-induced sepsis via reprogramming macrophage metabolism and regulating proinflammatory gene expression. Therefore, PFKFB3 is a potential target for the prevention and treatment of inflammatory diseases such as sepsis.
登录
查看更多内容
内皮腺苷 A2a 受体介导的糖酵解对于病理性视网膜血管生成至关重要
影响因子：
16.6
作者：
Liu Z;Yan S;Wang J;Xu Y;Wang Y;Zhang S;Xu X;Yang Q;Zeng X;Zhou Y;Gu X;Lu S;Fu Z;Fulton DJ;Weintraub NL;Caldwell RB;Zhang W;Wu C;Liu XL;Chen JF;Ahmad A;Kaddour-Djebbar I;Al-Shabrawey M;Li Q;Jiang X;Sun Y;Sodhi A;Smith L;Hong M;Huo Y
通讯作者：
Huo Y
糖酵解将视网膜血管生成微环境中骨髓细胞和内皮细胞的相互激活联系起来
影响因子：
17.1
作者：
Liu Z;Xu J;Ma Q;Zhang X;Yang Q;Wang L;Cao Y;Xu Z;Tawfik A;Sun Y;Weintraub NL;Fulton DJ;Hong M;Dong Z;Smith LEH;Caldwell RB;Sodhi A;Huo Y
通讯作者：
Huo Y
影响因子：
44.1
作者：
通讯作者：
--
DOI：
10.1073/pnas.1821401116
发表时间：
2019-07-02
影响因子：
11.1
作者：
Cao, Yapeng;Zhang, Xiaoyu;Huo, Yuqing
通讯作者：
Huo, Yuqing
影响因子：
29
作者：
Rodriguez, Arianne E.;Ducker, Gregory S.;Chandel, Navdeep S.
通讯作者：
Chandel, Navdeep S.