by Rituparna Mishra
Microglia are macrophage-like cells, which can be considered as immune sentinels that can send out a potent inflammatory response. Found in the central nervous system (CNS), these cells are highly dynamic, causing them to rely on only metabolic flexibility for their functionality. Their dynamic characteristic allows them to perform a variety of functions, such as blood vessel sprouting, control of neural precursor cell numbers, forming and eliminating synapses and constantly surveying the brain parenchyma. With high demand of ATP, microglial cells are required to produce quick energy. Some studies have shown through transcriptomic data, that microglia are highly flexible and can adapt to any metabolic profile depending on the substrate available. For instance, to sustain ATP under homeostatic conditions, microglia can bind with glutamine in the absence of glucose to keep homeostatic procedures continuous. Following the same concept, emerging roles for lactate as an alternative fuel for microglia has shown great potential.
Lactate is an organic acid and there has been much evidence to support its functions as a metabolite. It was first discovered by Swedish chemist Carl Wilhelm Scheele in 1780, and later used for the treatment of dry skin 1943. For all these years, it was believed that lactic acid is just a waste product of glycolysis, however, recent explorations have brought forth its potential as a key metabolite. Although it is known that glucose is majorly metabolised in the brain during development, other metabolites such as ketone bodies and lactate have also been catabolized in large amounts. In addition to that, as lactate can be utilised in both anaerobic and aerobic conditions, the lactate shuttle hypothesis allows the movement of lactate both intracellularly and intercellularly. One of the intercellular lactate shuttles that have been studied in depth was the astrocyte - neuron lactate shuttle (ANLS) hypothesis. Astrocytes are populations of cells, which have distinctive morphological and functional characteristics that differ within specific areas of the brain. This specific model suggests that lactate is produced in high concentrations in glycolytic astrocytes when synaptic activity occurs, and this lactate is then shuttled into neurons and oxidised into pyruvate for energy production. Previous studies have shown that oligodendrocytes can not only act as lactate recipients for astrocytes or providers to neurons, but also can independently use lactate under specific conditions and developmental phases. Recent studies have implied that microglia, that can adapt their metabolic status for functionality, can utilize lactate to sustain energy and control cell functions. This evidence suggests that microglia can not only produce lactate through glycolysis on lipopolysaccharide (LPS) stimulation but also can import it from extracellular spaces.
However, this importing process requires the presence of specific enzymes and transporters that allow efficient oxidation. The transporter that made this possible is the monocarboxylate transporter (MCTs), among which MCT1, MCT2 and MCT4 - encoded by the genes Slc16a1, Slc16a7, and Slc16a3, respectively - are most prominently found, and all these are capable of shuttling lactate, ketone bodies and pyruvate. MCT expression varies through different developmental stages and pathological states. For instance, MCT1 is expressed mostly by endothelial cells, ependymocytes and astrocytes, MCT2 is found particularly in neurons, and MCT4 is expressed by astrocytes. Similarly, in microglia, MCT4 is prominently found and MCT1 is found between the postnatal days - P4 and P14. Lactate oxidation is also dependent on the presence of lactate dehydrogenase - the enzyme which catalyses pyruvate and NADH to lactate and NAD⁺ in a dynamic equilibrium. Lactate dehydrogenase is found as either homotetramer or heterotetramer from two subunits LDHA and LDHB, wherein LDHB is responsible for the conversion of lactate into pyruvate, while LDHA is responsible for the opposite. It is reported that LDHB is one of the genes widely expressed in microglia, especially u=during the postnatal period, which indicates that lactate oxidation is more prominent during the developmental period. For example, in the adult hippocampus, LDHB concentrations are high in microglial cells - this suggests that LDHB is more suited for macrophages and is expressed more abundantly in those cells.
All this evidence indicates the possibility of lactate being imported into microglial cells to be oxidised into pyruvate by LDHB, to provide a fuel for the tricarboxylic acid (TCA) cycle, which supports microglial metabolism. Recent studies also showed that lactate moderates key microglia features such as proliferation, migration and phagocytosis. However, in vivo experiments are yet to uncover lactate’s potential in controlling microglial activities.
Although there hasn’t been much in depth coverage of lactate’s effects on microglia, its role in other macrophages, such as tumour associated macrophages (TAMs) has shown great results. Studies have found that lactate influences immune cells greatly in tumour microenvironments. In tumours, lactate builds up to very high concentrations due to the preferential glycolytic metabolism adopted by cancer cells. This lactate works collaboratively with other tumour - derived factors to reprogram immune cells into immune tolerant phenotypes, which therefore enhances tumour growth. TAMs can sense through various linked pathways the high presence of lactate being utilised by oxidative cancer cells to enhance the acidification of their lysosomes to regulate homeostatic functions in the brain. Microglia are heavily dependent on the use of lysosomes due to their degradation machinery, and therefore it is speculated that microglia could also utilize lactate in a way similar to how oxidative cancer cells do.
Microglia metabolic flexibility with respect to lactate still remains poorly examined in many fields, including their link in neurodegeneration and aging, in infections and brain injuries and in tumour microenvironment. Currently, the only available data is from transcriptome data and from in vitro studies. However, researchers are hoping to be able to perform in vivo studies that may uncover a greater potential for lactate in controlling microglial metabolism, and improving the metabolism flexibility of the cells.
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