Kir2.1-mediated membrane potential promotes nutrient acquisition and inflammation through regulation of nutrient transporters.
Kir2.1-mediated membrane potential promotes nutrient acquisition and inflammation through regulation of nutrient transporters.
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Kir2.1介导的膜电位通过调节营养转运蛋白促进营养获取和炎症
DOI：
10.1038/s41467-022-31149-y
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发表时间：
2022-06-21
影响因子：
16.6
通讯作者：
Wang, Di
中科院分区：
文献类型：
--
作者：
Yu, Weiwei;Wang, Zhen;Yu, Xiafei;Zhao, Yonghui;Xie, Zili;Zhang, Kailian;Chi, Zhexu;Chen, Sheng;Xu, Ting;Jiang, Danlu;Guo, Xingchen;Li, Mobai;Zhang, Jian;Fang, Hui;Yang, Dehang;Guo, Yuxian;Yang, Xuyan;Zhang, Xue;Wu, Yingliang;Yang, Wei;Wang, Di
免疫代谢有助于炎症，但活化的巨噬细胞如何获得细胞外营养素来刺激炎症在很大程度上是未知的。在这里，我们表明，由Kir2.1（一种内向整流K+通道）介导的巨噬细胞质膜电位（Vm）是营养获取和随后的代谢重编程促进炎症的重要决定因素。在缺乏Kir2.1活性的情况下，去极化的巨噬细胞Vm通过限制营养摄取和诱导自噬的营养保护中的伴随适应而导致热量限制状态，AMPK（腺苷5 '-单磷酸活化蛋白激酶）和GCN 2（一般对照非去阻遏蛋白2），其随后消耗在代谢应答性炎症基因簇的基因座处供给组蛋白甲基化的表观遗传底物，从而抑制它们的转录。Kir2.1介导的Vm通过调节质膜磷脂动力学促进营养转运蛋白如4F 2 hc和GLUT 1的细胞表面保留来支持营养摄取。Kir2.1的药理学靶向减轻了脓毒症模型中由LPS或细菌感染引发的炎症和人类样品中的无菌炎症。这些发现确定了巨噬细胞活化的离子控制，并推进了我们对Vm的免疫调节特性的理解，该特性将营养输入与炎症性疾病联系起来。
Immunometabolism contributes to inflammation, but how activated macrophages acquire extracellular nutrients to fuel inflammation is largely unknown. Here, we show that the plasma membrane potential (Vm) of macrophages mediated by Kir2.1, an inwardly-rectifying K+ channel, is an important determinant of nutrient acquisition and subsequent metabolic reprogramming promoting inflammation. In the absence of Kir2.1 activity, depolarized macrophage Vm lead to a caloric restriction state by limiting nutrient uptake and concomitant adaptations in nutrient conservation inducing autophagy, AMPK (Adenosine 5‘-monophosphate-activated protein kinase), and GCN2 (General control nonderepressible 2), which subsequently depletes epigenetic substrates feeding histone methylation at loci of a cluster of metabolism-responsive inflammatory genes, thereby suppressing their transcription. Kir2.1-mediated Vm supports nutrient uptake by facilitating cell-surface retention of nutrient transporters such as 4F2hc and GLUT1 by its modulation of plasma membrane phospholipid dynamics. Pharmacological targeting of Kir2.1 alleviated inflammation triggered by LPS or bacterial infection in a sepsis model and sterile inflammation in human samples. These findings identify an ionic control of macrophage activation and advance our understanding of the immunomodulatory properties of Vm that links nutrient inputs to inflammatory diseases.
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DOI：
10.1085/jgp.67.6.621
发表时间：
1976-06
期刊：
The Journal of general physiology
影响因子：
--
作者：
Hagiwara S;Miyazaki S;Rosenthal NP
通讯作者：
Rosenthal NP
DOI：
10.1042/bj20090428
发表时间：
2009-07-29
期刊：
The Biochemical journal
影响因子：
--
作者：
Hammond GR;Schiavo G;Irvine RF
通讯作者：
Irvine RF
影响因子：
3.3
作者：
Antonescu CN;Aguet F;Danuser G;Schmid SL
通讯作者：
Schmid SL
影响因子：
8.3
作者：
Gido, G;Kristian, T;Siesjo, BK
通讯作者：
Siesjo, BK
影响因子：
64.5
作者：
Chen, Kun;Liu, Juan;Cao, Xuetao
通讯作者：
Cao, Xuetao