A characteristic feature of inflamed tissue is hypoxia, which arises from elevated oxygen consumption and impaired perfusion. Inflammation is accompanied by metabolic reprogramming enabling immune and non-immune cells to meet increased bioenergetic and biosynthetic demands. Glycolysis is among the most ancient and fundamental metabolic pathways in biology. Hypoxia reduces mitochondrial oxidative phosphorylation, driving cells towards a reliance on glycolysis to sustain ATP production. This requires an increase in flux through the glycolytic pathway, which is mediated through rapid allosteric regulation of glycolytic enzymes, transcriptional upregulation of glucose transporters and glycolytic enzymes, and the formation of glycolytic enzyme complexes. In immune cells such as macrophages, neutrophils, and lymphocytes, enhanced glycolytic flux determines effector functions including, but not limited to, cytokine production, phagocytosis, migration, and antimicrobial activity, as well as maintaining bioenergetic homeostasis. Similarly, non-immune cells within inflamed tissues, including epithelial cells and stromal cells, utilize glycolysis to influence barrier function, tissue remodelling, and inflammation. In this review, we summarize our current understanding of how hypoxia drives glycolytic reprogramming during inflammation, examine the cell-type-specific impact of this, and discuss the therapeutic potential of targeting glycolytic pathways for inflammatory diseases.
Dehantschutter et al. (Fri,) studied this question.