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.

免疫代谢会导致炎症，但活化的巨噬细胞如何获得细胞外营养物质来促进炎症在很大程度上是未知的。在这里，我们表明由 Kir2.1（一种内向整流 K ⁺通道）介导的巨噬细胞质膜电位 (V _m )是营养获取和随后代谢重编程促进炎症的重要决定因素。在没有 Kir2.1 活性的情况下，去极化的巨噬细胞 V _m通过限制养分吸收和伴随的适应养分保存诱导自噬、AMPK（腺苷 5'-单磷酸活化蛋白激酶）和 GCN2（一般控制非抑制性 2），从而导致热量限制状态，随后耗尽表观遗传底物，在一组代谢反应性炎症基因的基因座，从而抑制它们的转录。Kir2.1 介导的 V _m通过调节质膜磷脂动力学，促进 4F2hc 和 GLUT1 等营养转运蛋白在细胞表面的保留，从而支持营养吸收。Kir2.1 的药理学靶向缓解了脓毒症模型中由 LPS 或细菌感染引发的炎症以及人类样本中的无菌炎症。这些发现确定了巨噬细胞活化的离子控制，并促进了我们对将营养输入与炎症性疾病联系起来的 V _{m的免疫调节特性的理解。}