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

Weiwei Yu1,2, Zhen Wang1,2, Xiafei Yu3

  • 1Institute of Immunology and Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, 310058, P. R. China.

Nature Communications
|June 21, 2022
PubMed

Insights

The inwardly-rectifying potassium channel Kir2.1 controls macrophage nutrient uptake and inflammation by regulating plasma membrane potential. Targeting Kir2.1 reduces inflammation in sepsis and sterile inflammatory conditions.

Area of Science:

  • Immunometabolism
  • Cellular Physiology
  • Inflammation Biology

Background:

  • Macrophage activation drives inflammation by reprogramming cellular metabolism.
  • Mechanisms by which activated macrophages acquire extracellular nutrients to fuel inflammation remain poorly understood.

Purpose of the Study:

  • To investigate the role of plasma membrane potential (Vm) in macrophage nutrient acquisition and metabolic reprogramming during inflammation.
  • To identify specific ion channels involved in regulating Vm and nutrient uptake in macrophages.

Main Methods:

  • Utilized electrophysiology to assess macrophage plasma membrane potential (Vm).
  • Investigated the function of Kir2.1 channels in nutrient transporter localization and function.
  • Employed pharmacological inhibition of Kir2.1 in preclinical models of sepsis and sterile inflammation.

Main Results:

  • Kir2.1-mediated Vm is crucial for nutrient acquisition and metabolic reprogramming that promotes inflammation.
  • Loss of Kir2.1 activity leads to a caloric restriction state, inducing nutrient conservation pathways (autophagy, AMPK, GCN2).
  • Kir2.1 supports nutrient transporter (4F2hc, GLUT1) cell-surface retention via plasma membrane dynamics.
  • Pharmacological targeting of Kir2.1 suppressed LPS-induced and bacterial infection-induced inflammation in a sepsis model, as well as sterile inflammation in human samples.

Conclusions:

  • Kir2.1-mediated plasma membrane potential is a key regulator of macrophage activation and nutrient uptake.
  • Targeting Kir2.1 offers a potential therapeutic strategy for inflammatory diseases by modulating immunometabolism.

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