Each transporter prefers import or export of lactate however, the transport direction of both systems depends on the lactate gradient, favouring lactate import when extracellular lactate is high, such as in inflamed tissues. Structurally, these transporters contain two six-helix bundles, which constitute their transmembrane domain. Lactate stereoselective transport across plasma membranes is mediated by six described solute carrier transporters that perform proton-lactate symport (monocarboxylate transporters: SLC16A1, SLC16A7, SLC16A8 and SLC16A3, also known as MCT1–4) and sodium-dependent transporters (SLC5A8 and SLC5A12, also known as SMCT1–2). These tissue lactate concentrations in solid tumours were measured using mass spectrometry and imaging bioluminescence (measurements in µmol/g), followed by conversion to mM considering the tumour water content. Tissue lactate concentrations are often many folds higher than blood lactate, a scenario seen in cancer and inflammatory settings where blood lactate is frequently normal, but tissue lactate may reach 15–40 mM ( Table 1). Hypoxia and hypoperfusion (decreased blood flow) are the main causes of increased lactate, other contributing factors being hypermetabolism, and mitochondrial or liver dysfunction which impact clearance of lactate. The aetiology of hyperlactataemia is mixed and dependent on individual circumstances in body compartments. However, clinical trials targeting clearance of lactate as a marker of resuscitation in sepsis have failed to demonstrate any benefit. Today, lactate is routinely measured and used as a biomarker for disease severity in critically ill patients. Lactate was originally considered a by-product of cell metabolism, however, there is increasing evidence that it can act as a signalling molecule impacting cell behaviour and function. Microbial species contain both LDH forms and can, therefore, produce both lactate isoforms, whereas in vertebrates l-LDH and consequently l-lactate prevail. Lactate comprises two stereoisomers, d(−) lactate and l(+) lactate, which are metabolised by d-LDH and l-LDH, respectively. In this process, ATP and NADH molecules are generated, creating usable energy for the cell. In this cytosolic central metabolic pathway, one glucose molecule is broken down into two pyruvate molecules, which are converted into lactate by lactate dehydrogenase (LDH). Lactate is the anion form of lactic acid and the main product generated at the end of anaerobic glycolysis as well as of aerobic glycolysis in highly proliferative cells, also known as the Warburg effect. Lactic acid (C 3H 6O 3) was first reported in sour milk in 1780. Here, we will discuss the preliminary research that has been carried out in the context of cancer, autoimmunity and inflammation. The ubiquitous presence of lactate in the context of infection and the ability of both host cells and pathogens to sense and respond to it, makes manipulation of lactate a potential novel therapeutic strategy. This review will cover lactate secretion and sensing in humans and microbes, and will discuss the existing evidence supporting a role for lactate in pathogen growth and persistence, together with lactate's ability to impact the orchestration of effective immune responses. Infection can alter this intricate balance, and the presence of lactate transporters in most human cells including immune cells, as well as in a variety of pathogens (including bacteria, fungi and complex parasites) demonstrates the importance of this metabolite in regulating host–pathogen interactions. Lactate can be released and used by host cells, by pathogens and commensal organisms, thus being essential for the homeostasis of host–microbe interactions. Lactate is the main product generated at the end of anaerobic glycolysis or during the Warburg effect and its role as an active signalling molecule is increasingly recognised.
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