2. Academic Validation
  3. 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

  • Nat Commun. 2022 Jun 21;13(1):3544. doi: 10.1038/s41467-022-31149-y.
Weiwei Yu  # 1 2,  Zhen Wang  # 1 2,  Xiafei Yu  # 3,  Yonghui Zhao 4,  Zili Xie 4,  Kailian Zhang 1,  Zhexu Chi 1,  Sheng Chen 1,  Ting Xu 1,  Danlu Jiang 1,  Xingchen Guo 4,  Mobai Li 1,  Jian Zhang 1,  Hui Fang 1,  Dehang Yang 1,  Yuxian Guo 1,  Xuyan Yang 5,  Xue Zhang 6,  Yingliang Wu 4,  Wei Yang 7,  Di Wang 8 9
Affiliations

Affiliations

  • 1 Institute of Immunology and Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, 310058, P. R. China.
  • 2 Liangzhu Laboratory, Zhejiang University Medical Center, 1369 West Wenyi Road, Hangzhou, P. R. China.
  • 3 Department of Biophysics, and Department of Neurology of the Fourth Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310058, P. R. China.
  • 4 State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan, 430072, P. R. China.
  • 5 Department of Rheumatology of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310058, P. R. China.
  • 6 Department of Pathology and Pathophysiology, Zhejiang University School of Medicine, Hangzhou, 310058, P. R. China.
  • 7 Department of Biophysics, and Department of Neurology of the Fourth Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310058, P. R. China. yangwei@zju.edu.cn.
  • 8 Institute of Immunology and Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, 310058, P. R. China. diwang@zju.edu.cn.
  • 9 Liangzhu Laboratory, Zhejiang University Medical Center, 1369 West Wenyi Road, Hangzhou, P. R. China. diwang@zju.edu.cn.
  • # Contributed equally.
PMID: 35729093 DOI: 10.1038/s41467-022-31149-y
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.

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