Kir2.1-mediated membrane potential promotes nutrient acquisition and inflammation through regulation of nutrient transporters

Author:

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 XueORCID,Wu Yingliang,Yang Wei,Wang DiORCID

Abstract

AbstractImmunometabolism 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.

Funder

National Natural Science Foundation of China

China Postdoctoral Science Foundation

Publisher

Springer Science and Business Media LLC

Subject

General Physics and Astronomy,General Biochemistry, Genetics and Molecular Biology,General Chemistry,Multidisciplinary

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