Lactate's impact on immune cells in sepsis: unraveling the complex interplay

Abstract

Lactate significantly impacts immune cell function in sepsis and septic shock, transcending its traditional view as just a metabolic byproduct. This review summarizes the role of lactate as a biomarker and its influence on immune cell dynamics, emphasizing its critical role in modulating immune responses during sepsis. Mechanistically, key lactate transporters like MCT1, MCT4, and the receptor GPR81 are crucial in mediating these effects. HIF-1α also plays a significant role in lactate-driven immune modulation. Additionally, lactate affects immune cell function through post-translational modifications such as lactylation, acetylation, and phosphorylation, which alter enzyme activities and protein functions. These interactions between lactate and immune cells are central to understanding sepsis-associated immune dysregulation, offering insights that can guide future research and improve therapeutic strategies to enhance patient outcomes.

Keywords: immune cells; immune response; immunosuppression; inflammation; lactate; lactic acid; lactylation; sepsis.

Figure 1

Major pathophysiological mechanisms of hyperlactatemia in sepsis/septic shock. The diagram illustrates the complex interplay between the immune response, tissue hypoxia, and metabolic alterations during sepsis and septic shock. Activation of immune cells leads to increased cytokine production, which along with epinephrine stimulation, enhances glycolysis and stabilizes hypoxia-inducible factor 1-alpha (HIF1α), resulting in increased lactate production. Tissue hypoxia due to microvascular injury further exacerbates lactate production. Concurrently, the Cori cycle in the liver and kidneys converts lactate back to glucose, but this process is often impaired in sepsis due to organ dysfunction, leading to decreased lactate catabolism and contributing to hyperlactatemia. This condition is further complicated by mitochondrial dysfunction, which impairs the conversion of pyruvate into the tricarboxylic acid (TCA) cycle intermediates, exacerbating lactate accumulation. Hyperlactatemia serves as both a marker of metabolic distress and a target for therapeutic intervention in sepsis management. Red colored arrows indicate activated events, while blue colored arrows indicate suppressed events, following sepsis/septic shock.

Figure 2

Lactate regulates lymphocyte function. (A) Lactate regulates CD4⁺ T cell function by the following mechanisms: inhibiting glycolysis and thus migration, disrupting the balance between NAD⁺ and NADH, mediating an increase in STAT3 phosphorylation by affecting PKM2 nuclear translocation and facilitating fatty acid synthesis, thereby increasing IL-17 production, and regulating gene expression by lactylation of Ikzf1, which facilitates differentiation to Th17 cells. (B) Lactate modulates CD8⁺ T cells by mechanisms such as, inhibiting glycolysis and thus migration, disrupting the balance between NAD⁺ and NADH, affecting pyruvate metabolism and thus reducing cytotoxicity, inhibiting histone deacetylase (HDAC) and thus promoting acetylation of histone H3K27 and thus increasing anti-tumor immunity, and its inhibition of the glycolytic enzyme GAPDH contributes to the production of IFN-γ, but appears to inhibit TCR-mediated IFN-γ production. (C) For Treg cells, in addition to limiting glycolysis, lactate binding to GPR81 enhances their infiltrative capacity, it improves PD1 expression by increasing the NAFT1 nuclear translocation mechanism, and it mediates high CTLA4 expression by up-regulating Foxp3, and lactate also promotes the lactylation of MOESIN to improve Treg function. (D) Lactate acts on B cells by the following mechanisms: promotion of germinal center function, inhibition of glycolysis, promotion of proliferation through increased ANG expression or positive feedback through miR-223-mediated lactate production, and lactate mediates the acetylation of histone H3K27 and thus promotes IgG class switching. Red colored arrows indicate activated events, while blue colored arrows indicate suppressed events, by lactate during sepsis/septic shock.

Figure 3

Lactate regulates macrophage function. In macrophages, lactate inhibits glycolysis, and its binding to GPR81 inhibits TLR-mediated pro-inflammatory responses via NF-kB, and it promotes Arg-1 and Vegf-α gene expression via up-regulation of HIF-1α, and the elevation of Arg-1 promotes histone lactylation, and lactate maintains its anti-inflammatory function via inhibition of HDAC and promotion of histone acetylation via TCA cycling. In addition, lactate can maintain anti-inflammatory function by inhibiting HDAC and promoting TCA cycle to promote histone acetylation, whereas for non-histone proteins, such as HMGB1, lactate can mediate lactylation and acetylation through β-arrestin2 promotion of p300/CBP and LATS/YAP-mediated inhibition of SIRT1.

Figure 4

Lactate regulates NK cell, dendritic cell and neutrophil function. In NK cells, lactate inhibits glycolysis, suppresses mitochondrial function, inhibits the expression of NFAT and NKp46, promotes apoptosis and attenuates their ability to secrete inflammatory factors; whereas, for NK-T cells, the increase in histone lactylation promotes the expression of Foxp3. In dendritic cells, lactate inhibited glycolysis, inhibited CCR-7 and thus migration, lactate inhibited MHC II function through GPR81 signaling, and in addition GPR81-mediated Ca2+ mobilization inhibited IFN-α secretion. In mesangial cells, lactate maintains their immune function and promotes their NET formation.