Crosstalk between glucose metabolism, lactate production and immune response modulation

Metabolites of glycolytic metabolism have been identified as signaling molecules and regulators of gene expression, in addition to their basic function as major energy and biosynthetic source. Immune cells reprogram metabolic pathways to cater to energy and biosynthesis demands upon activation. Most lymphocytes, including inflammatory M1 macrophages, mainly shift from oxidative phosphorylation to glycolysis, whereas regulatory T cells and M2 macrophages preferentially use the tricarboxylic acid (TCA) cycle and have reduced glycolysis. Recent studies have revealed the non-metabolic signaling functions of intermediates of the mitochondrial pathway and glycolysis. The roles of citrate, succinate and itaconate in immune response, including post-translational modifications of proteins and macrophages activation, have been highlighted. As an end product of glycolysis, lactate has received considerable interest from researchers. In this review, we specifically focused on studies exploring the integration of lactate into immune cell biology and associated pathologies. Lactate can act as a double-edged sword. On one hand, activated immune cells prefer to use lactate to support their function. On the other hand, accumulated lactate in the tissue microenvironment acts as a signaling molecule that restricts immune cell function. Recently, a novel epigenetic change mediated by histone lysine lactylation has been proposed. The burgeoning researches support the idea that histone lactylation participates in diverse cellular events. This review describes glycolytic metabolism, including the immunoregulation of metabolites of the TCA cycle and lactate. These latest findings strengthen our understanding on tumor and chronic inflammatory dis-eases and offer potential therapeutic options.

Automated summary

Metabolites of glycolytic metabolism play roles as signaling molecules and regulators of gene expression in immune cells. Recent studies have revealed the non-metabolic signaling functions of intermediates of the mitochondrial pathway and glycolysis. Lactate, as the end product of glycolysis, plays important roles in immune cell biology and associated pathologies.