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

Weiwei Yu, Zhen Wang, Xiafei Yu, Yonghui Zhao, Zili Xie, Kailian Zhang, Zhexu Chi, Sheng Chen, Ting Xu, Danlu Jiang, Xingchen Guo, Mobai Li, Jian Zhang, Hui Fang, Dehang Yang, Yuxian Guo, Xuyan Yang, Xue Zhang, Yingliang Wu, Wei Yang () and Di Wang ()
Additional contact information
Weiwei Yu: Zhejiang University School of Medicine
Zhen Wang: Zhejiang University School of Medicine
Xiafei Yu: Zhejiang University School of Medicine
Yonghui Zhao: Wuhan University
Zili Xie: Wuhan University
Kailian Zhang: Zhejiang University School of Medicine
Zhexu Chi: Zhejiang University School of Medicine
Sheng Chen: Zhejiang University School of Medicine
Ting Xu: Zhejiang University School of Medicine
Danlu Jiang: Zhejiang University School of Medicine
Xingchen Guo: Wuhan University
Mobai Li: Zhejiang University School of Medicine
Jian Zhang: Zhejiang University School of Medicine
Hui Fang: Zhejiang University School of Medicine
Dehang Yang: Zhejiang University School of Medicine
Yuxian Guo: Zhejiang University School of Medicine
Xuyan Yang: Zhejiang University School of Medicine
Xue Zhang: Zhejiang University School of Medicine
Yingliang Wu: Wuhan University
Wei Yang: Zhejiang University School of Medicine
Di Wang: Zhejiang University School of Medicine

Nature Communications, 2022, vol. 13, issue 1, 1-18

Abstract: Abstract 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.

Date: 2022
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DOI: 10.1038/s41467-022-31149-y

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