Lactate and lactylation in macrophage metabolic reprogramming: current progress and outstanding issues

Abstract

It is commonly known that different macrophage phenotypes play specific roles in different pathophysiological processes. In recent years, many studies have linked the phenotypes of macrophages to their characteristics in different metabolic pathways, suggesting that macrophages can perform different functions through metabolic reprogramming. It is now gradually recognized that lactate, previously overlooked as a byproduct of glycolytic metabolism, acts as a signaling molecule in regulating multiple biological processes, including immunological responses and metabolism. Recently, lactate has been found to mediate epigenetic changes in macrophages through a newfound lactylation modification, thereby regulating their phenotypic transformation. This novel finding highlights the significant role of lactate metabolism in macrophage function. In this review, we summarize the features of relevant metabolic reprogramming in macrophages and the role of lactate metabolism therein. We also review the progress of research on the regulation of macrophage metabolic reprogramming by lactylation through epigenetic mechanisms.

Keywords: Post-translational modification (PTM); lactate; lactylation; macrophage; metabolic reprogramming.

Figure 1

Relevant enzymes in macrophage glycolysis and their regulatory mechanisms (Created with BioRender.com).

Figure 2

Lactate’s mechanisms in shaping tumor-associated macrophages into an M2-like phenotype. (A) Lactate promotes Arg-1 and VEGF expression through stabilization/activation of HIF-1α. (B) Proton-sensing GPR65/GPR132 activated by acidic TME from extracellular lactate induces M2-like gene expression via the cAMP-ICER pathway. (C) Lactate-activated mTORC1 negatively regulates TFEB, which reduces HIF-2α degradation by down-regulating ATP6V0D2 expression on the surface of the lysosome, thereby regulating immunosuppressive and pro-angiogenic M2-like gene expression. (D) Lactate-activated mTORC2-AKT pathway induces TAM to a pro-invasive M2-like phenotype. (E) Lactate activates the ERK-STAT3 pathway by phosphorylating ERK, which in turn induces anti-inflammatory and pro-angiogenic M2-like phenotypes. (F) GPR81/HCAR1 is activated by physiological concentrations of extracellular lactic acid, which induces PD-L1 expression via down-regulation of the cAMP-PKA pathway, thereby promoting tumor immune evasion. (G) Lactate promotes histone lactylation modification (yellow circle) at the promoter H3K18 site of Arg-1, VEGF and other M2-like genes in TAM to up-regulate their expression, thereby inducing an M2-like phenotype in TAM. (Created with BioRender.com).

Figure 3

Role of the Warburg effect as well as histone and non-histone lactylation mediated by lactate in the regulation of macrophage phenotype. (A) HIF-1α induced by activation of NF-κB signaling after exposure to pro-inflammatory stimuli such as LPS and hypoxia can undergo nuclear translocation and form a complex by interacting with HIF-1β and PKM2 dimer, which also undergo nuclear translocation. This complex induces the expression of M1-like genes by acting on the HRE at the promoters of the target genes, polarizing macrophages to the M1 phenotype. (B) Activation of M1 macrophages upregulates the expression of iNOS, which metabolizes arginine to NO. Accumulation of NO damages OXPHOS, leading to enhanced glycolysis in M1 macrophages. (C) LPS-recognized TLR activates PI3K-AKT via BCAP, which reduces inflammation by phosphorylating and inhibiting downstream molecules GSK3β and FOXO1, as well as enhances glycolysis to produce lactate. (D) Lactate (L-lactate) in the cytoplasm can be either endogenous lactate that accumulates via macrophage glycolysis production or exogenous lactate that is taken up from the extracellular environment via MCT1 at the plasma membrane. (E) Histone lactylation is shown by the blue arrow. Lactate in M1 macrophages can be catalyzed by currently unidentified enzymes to generate Lactyl-CoA, which initiates an endogenous “lactate clock” after entering the nucleus, and M2 signature genes modified by lactylation are activated for expression, resulting in cells exhibiting M2-like features. (F) The glycolytic byproduct MGO binds to glutathione via GLO1 to form LGSH. LGSH cannot produce D-lactate in the absence of GLO2, but rather indirectly modifies glycolytic enzymes through non-enzymatic lysine lactoylation, which negatively regulates glycolysis by inhibiting glycolytic enzymes (as shown by the red arrows). (G) The red arrows show the processes in which non-histone lactylation is involved in regulation. Lactate accumulation from M1 macrophage glycolysis can result in the lactylation of PKM2, which activates the PKM2 dimer to a tetrameric form and exerts an inhibitory effect on macrophage glycolysis. In addition, the stability of HIF-1α in M1 macrophages may also be regulated by lactylation modification. (Created with BioRender.com).