L(+)-Lactic acid: Characteristics, Physiological Functions and Effects on Macrophage Polarization

General Description

L(+)-Lactic acid is a versatile molecule with significant roles in the human body. It serves as an energy substrate, impacts epigenetics, and acts as a soluble hormone sensed by receptors. Its production and transport involve specific proteins. Functionally, it influences various signaling pathways in muscle cells, neurons, and cancer cells, playing roles in metabolic responses, neuronal plasticity, and cancer development. Notably, L(+)-Lactic acid affects macrophage polarization, promoting M2-like phenotype in different conditions, such as cancer and inflammatory diseases. Its effects on macrophages are crucial in inflammation, tissue repair, and immune regulation, highlighting its relevance in both physiological and pathological contexts.

Figure 1. L(+)-Lactic acid

Characteristics

L(+)-Lactic acid is a versatile molecule that plays important roles in the human body as both a nutrient and a signaling molecule. It has several key characteristics that make it unique. First, it is an energy-rich substrate, meaning that it can be used as a source of energy by cells. Second, it is capable of affecting epigenetics, which are changes in gene expression that do not involve alterations to the underlying DNA sequence. Finally, L(+)-Lactic acid can act as a soluble hormone that is "sensed" by membrane receptors. The production of L(+)-Lactic acid occurs in the cytoplasm of cells, where it is then secreted through the plasma membrane. This transport is mediated by lactate-dependent transmembrane protein (MCT) or sodium-dependent co-transport (SLC5A8, SlC5A12). There are four members of the MCT family, each with different substrate specificity, transport rate, and expression pattern. MCT1 is responsible for regulating the transport of lactate across the plasma membrane in most lactate-producing tissues, while MCT4 is responsible for exporting lactate to the extracellular space. L(+)-Lactic acid also plays an important role in signaling transduction pathways in the human body. These processes are mediated by receptors or transporters that are activated by lactic acid. Overall, L(+)-Lactic acid is a versatile molecule with unique characteristics that make it essential to many physiological processes in the human body. ¹

Physiological Functions

L(+)-Lactic acid is a type of organic acid produced in the body's muscles during intense exercise or periods of low oxygen, such as hypoxia. It has been found to play a crucial role in the activation of different signaling pathways in various cells. In muscle cells, L(+)-Lactic acid has been shown to coordinate adaptive metabolic responses during endurance training by inducing an increase in MCT1 expression in reactive oxygen species(ROS)-dependent/ NRF2-mediated signaling pathway. In neurons, L(+)-Lactic acid derived from astrocytes alters the intracellular redox state and stimulates the expression of NMDA receptor and ERK1/2-mediated genes associated with neuronal plasticity. Additionally, L(+)-Lactic acid can stabilize HIF-1α by inhibiting prolyl hydroxylase2(PHD2), thus ensuring cell adaptation under hypoxia. In cancer cells, L(+)-Lactic acid promotes the expression of VEGF mediated by HIF-1α and enhances the decomposition of glutamine. It also induces the stabilization of HIF-2α. Furthermore, lactic acid has been found to regulate the expression of homeostasis genes in macrophages through a histone post-translational modification function called histone lysine lactation. Overall, L(+)-Lactic acid plays a vital role in regulating cellular functions in various cells under both physiological and pathological conditions. Its multiple functions make it a valuable area of research for potential therapeutic interventions. ²

Effects on Macrophage Polarization

L(+)-Lactic acid has been found to have significant effects on macrophage polarization. Macrophages are immune cells that play a crucial role in inflammation, tissue repair, and immune response regulation. The concentration of L(+)-Lactic acid in various physiological and pathological conditions can greatly influence macrophage behavior and disease progression. Studies have shown that L(+)-Lactic acid promotes the polarization of M2-like macrophages, which are associated with tissue repair and immune regulation. In cancer tissues, the high concentration of lactic acid, up to 20-40mM, has been found to induce M2-like macrophage polarization. This promotes tumor growth and angiogenesis through metabolic reprogramming and the expression of vascular endothelial growth factor (VEGF). L(+)-Lactic acid has also been observed to stimulate the proliferation and differentiation of muscle progenitor cells, promoting muscle regeneration. Inflammatory diseases, such as atherosclerotic plaques or rheumatic synovial fluid, where L(+)-Lactic acid concentration is elevated, can lead to the polarization of macrophages into an M2-like immunophenotype. This immunophenotype is associated with immune system dysfunctions in the pathogenesis of these diseases. The exact molecular mechanisms by which lactic acid induces macrophage polarization are not yet fully understood. However, recent studies have suggested that lactic acid may exert its effects through epigenetic mechanisms, such as histone lysine lactation and acetylation. Overall, the accumulation of L(+)-Lactic acid in various tissues can significantly impact macrophage polarization, influencing disease progression, tissue repair, and immune response regulation. Further research is needed to fully elucidate the molecular mechanisms underlying the effects of lactic acid on macrophages. ²

Reference

1. Certo M, Marone G, de Paulis A, Mauro C, Pucino V. Lactate: Fueling the fire starter. Wiley Interdiscip Rev Syst Biol Med. 2020; 12(3): e1474.

2. Zhou HC, Xin-Yan Yan, Yu WW, et al. Lactic acid in macrophage polarization: The significant role in inflammation and cancer. Int Rev Immunol. 2022;41(1):4-18.