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

Potassium channels and membrane potential may influence macrophage function during inflammation. Here the authors show that the Kir2.1 potassium channel affects macrophage metabolism by altering cell surface retention of nutrient transporters and subsequently regulates inflammatory disease responses. 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 (V-m) 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 V-m 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 V-m 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 V-m that links nutrient inputs to inflammatory diseases.

Automated summary

This study reveals that the Kir2.1 potassium channel regulates macrophage metabolism and inflammatory responses. The activity of this channel affects nutrient uptake and subsequent metabolic reprogramming, which promotes inflammation. Targeting Kir2.1 with drugs can alleviate inflammation triggered by infections. These findings advance our understanding of the role of membrane potential in immune function and provide potential therapeutic strategies for inflammatory diseases.