Microglial metabolic flexibility: emerging roles for lactate
Authors: Katia Monsorno, An Buckinx, Rosa C. Paolicelli
Journal: Trends in Endocrinology and Metabolism (2022)

Microglia, the innate immune cells of the central nervous system (CNS), are highly dynamic and rely on metabolic flexibility to sustain their cellular functions.In addition to energy production, metabolic pathways are important in regulating immune cell function by influencing the inflammatory profile and phagocytic capacity of the cell.Recent single cell RNA-seq datasets indicate that microglia have all the machinery for rapid metabolic reprogramming and for the utilization of different bioenergetic substrates.Lactate is emerging as a key brain metabolite associated with synaptic plasticity and CNS pathologies, and recent studies highlight its possible role in controlling microglial function.Targeting microglial lactate metabolism might prove to be an effective approach to modulate microglia in several CNS diseases. Microglia, the resident macrophages of the central nervous system (CNS), play important functions in the healthy and diseased brain. In the emerging field of immunometabolism, progress has been made in understanding how cellular metabolism can orchestrate the key responses of tissue macrophages, such as phagocytosis and inflammation. However, very little is known about the metabolic control of microglia. Lactate, now recognized as a crucial metabolite and a central substrate in metabolic flexibility, is emerging not only as a novel bioenergetic fuel for microglial metabolism but also as a potential modulator of cellular function. Parallels with macrophages will help in understanding how microglial lactate metabolism is implicated in brain physiology and pathology, and how it could be targeted for therapeutic purposes. Microglia, the resident macrophages of the central nervous system (CNS), play important functions in the healthy and diseased brain. In the emerging field of immunometabolism, progress has been made in understanding how cellular metabolism can orchestrate the key responses of tissue macrophages, such as phagocytosis and inflammation. However, very little is known about the metabolic control of microglia. Lactate, now recognized as a crucial metabolite and a central substrate in metabolic flexibility, is emerging not only as a novel bioenergetic fuel for microglial metabolism but also as a potential modulator of cellular function. Parallels with macrophages will help in understanding how microglial lactate metabolism is implicated in brain physiology and pathology, and how it could be targeted for therapeutic purposes. Microglia, the innate immune cells of the CNS, are key players in both physiological and pathological contexts. They actively participate in an ever-growing list of biological processes, including blood vessel sprouting, control of neural precursor cell numbers, the formation and elimination of synapses, and ceaseless monitoring of the brain parenchyma [1.Sierra A. et al.Cien anos de microglia: milestones in a century of microglial research.Trends Neurosci. 2019; 42: 778-792Abstract Full Text Full Text PDF PubMed Scopus (62) Google Scholar]. To ensure constant surveillance, microglia rapidly extend and retract their processes via continuous energy-dependent cytoskeleton rearrangement [2.Davalos D. et al.ATP mediates rapid microglial response to local brain injury in vivo.Nat. Neurosci. 2005; 8752–728Crossref Scopus (2539) Google Scholar,3.Nimmerjahn A. et al.Resting microglial cells are highly dynamic surveillants of brain parenchyma in vivo.Science. 2005; 308: 1314-1318Crossref PubMed Scopus (3647) Google Scholar]. 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Although an extensive literature covers the link between metabolic reprogramming and immune function in peripheral macrophages (reviewed in [7.Van den Bossche J. et al.Macrophage immunometabolism: where are we (going)?.Trends Immunol. 2017; 38: 395-406Abstract Full Text Full Text PDF PubMed Scopus (411) Google Scholar]), much less is currently known about microglial regulation of energy metabolism. Most current knowledge about microglial metabolism relies on transcriptomic data, or has been extrapolated from studies on immortalized cell lines or primary cultures. In principle, microglia express all the key enzymes implicated in the major metabolic pathways, indicative of considerable plasticity [8.Pinto A.R. et al.An abundant tissue macrophage population in the adult murine heart with a distinct alternatively-activated macrophage profile.PLoS One. 2012; 7e36814Crossref PubMed Scopus (205) Google Scholar,9.Zhang Y. et al.An RNA-sequencing transcriptome and splicing database of glia, neurons, and vascular cells of the cerebral cortex.J. Neurosci. 2014; 34: 11929-11947Crossref PubMed Scopus (2637) Google Scholar]. Thus, the specific metabolic profile adopted by microglia at any given moment likely depends on the availability of the bioenergetic substrates and on the expression of the metabolic machinery in different microglial states. This is further supported by the observation that, at least in mice, genes related to metabolic pathways are differentially expressed in microglia according to the age of the animal and the CNS structure examined [9.Zhang Y. et al.An RNA-sequencing transcriptome and splicing database of glia, neurons, and vascular cells of the cerebral cortex.J. Neurosci. 2014; 34: 11929-11947Crossref PubMed Scopus (2637) Google Scholar,10.Hammond T.R. et al.Single-cell RNA sequencing of microglia throughout the mouse lifespan and in the injured brain reveals complex cell-state changes.Immunity. 2019; 50: 253-271Abstract Full Text Full Text PDF PubMed Scopus (599) Google Scholar]. Under homeostatic conditions, microglia mostly rely on oxidative metabolism of glucose, which can be replaced by alternative metabolic pathways in the case of scarce glucose availability. In particular, in the absence of glucose, microglia can rapidly shift to other substrates, such as glutamine, to sustain ATP production and preserve homeostatic surveillance [6.Bernier L.P. et al.Microglial metabolic flexibility supports immune surveillance of the brain parenchyma.Nat. Commun. 2020; 11: 1559Crossref PubMed Scopus (59) Google Scholar]. Consistent with this emerging concept of microglial metabolic flexibility, a role for lactate as an alternative metabolic fuel in microglia is highly plausible yet poorly explored. There is extensive evidence that glucose is the main substrate metabolized in adult brain [11.Hyder F. et al.Uniform distributions of glucose oxidation and oxygen extraction in gray matter of normal human brain: no evidence of regional differences of aerobic glycolysis.J. Cereb. Blood Flow Metab. 2016; 36: 903-916Crossref PubMed Scopus (51) Google Scholar,12.Dienel G.A. Brain glucose metabolism: integration of energetics with function.Physiol. 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Indeed, lactate produced by highly glycolytic cells can be shuttled to adjacent cells, where (i) it can be oxidized to pyruvate and serve as a major energy source, (ii) it can act as gluconeogenic precursor, enabling the net synthesis of glucose, (iii) it can work as a signaling molecule [20.Brooks G.A. Lactate shuttles in nature.Biochem. Soc. Trans. 2002; 30: 258-264Crossref PubMed Scopus (279) Google Scholar,21.Brooks G.A. Cell–cell and intracellular lactate shuttles.J. Physiol. 2009; 587: 5591-5600Crossref PubMed Scopus (444) Google Scholar], and (iv) it can modulate transcriptional activity through an epigenetic modification named lactylation [22.Zhang D. et al.Metabolic regulation of gene expression by histone lactylation.Nature. 2019; 574: 575-580Crossref PubMed Scopus (442) Google Scholar]. One of the best-studied intercellular lactate shuttles refers to the so-called astrocyte–neuron lactate shuttle (ANLS) hypothesis [23.Pellerin L. et al.Expression of monocarboxylate transporter mRNAs in mouse brain: support for a distinct role of lactate as an energy substrate for the neonatal vs. adult brain.Proc. Natl. Acad. Sci. U. S. A. 1998; 95: 3990-3995Crossref PubMed Scopus (240) Google Scholar,24.Pellerin L. Magistretti P.J. Glutamate uptake into astrocytes stimulates aerobic glycolysis: a mechanism coupling neuronal activity to glucose utilization.Proc. Natl. Acad. Sci. U. S. A. 1994; 91: 10625-10629Crossref PubMed Scopus (2004) Google Scholar]. According to this model, lactate is largely produced by highly glycolytic astrocytes upon sensing synaptic activity. Lactate is then shuttled into neurons and is used to generate energy through its conversion to pyruvate, ultimately fueling oxidative phosphorylation. More recently, oligodendrocytes have also been proposed to act either as lactate providers to neurons [25.Lee Y. et al.Oligodendroglia metabolically support axons and contribute to neurodegeneration.Nature. 2012; 487: 443-448Crossref PubMed Scopus (968) Google Scholar], or as lactate recipients from astrocytes, to fuel fatty acid synthesis and myelin production [26.Rinholm J.E. et al.Regulation of oligodendrocyte development and myelination by glucose and lactate.J. Neurosci. 2011; 31: 538-548Crossref PubMed Scopus (219) Google Scholar]. Previous studies have shown that oligodendrocytes – and also astrocytes themselves – can utilize lactate in specific conditions and developmental phases [26.Rinholm J.E. et al.Regulation of oligodendrocyte development and myelination by glucose and lactate.J. 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In vitro data indicate that microglia can utilize lactate as a key metabolite and signaling molecule to sustain energy demand and control cellular function [30.Nagy A.M. et al.Versatility of microglial bioenergetic machinery under starving conditions.Biochim. Biophys. Acta Bioenerg. 2018; 1859: 201-214Crossref PubMed Scopus (15) Google Scholar,31.Liu Y. et al.Functions of lactate in the brain of rat with intracerebral hemorrhage evaluated with MRI/MRS and in vitro approaches.CNS Neurosci. Ther. 2020; 26: 1031-1044Crossref PubMed Scopus (9) Google Scholar]. This experimental evidence suggests that microglia are not only able to produce lactate through glycolysis, for instance upon lipopolysaccharide (LPS) stimulation [28.Voloboueva L.A. et al.Inflammatory response of microglial BV-2 cells includes a glycolytic shift and is modulated by mitochondrial glucose-regulated protein 75/mortalin.FEBS Lett. 2013; 587: 756-762Crossref PubMed Scopus (113) Google Scholar,29.Gimeno-Bayón J. et al.Glucose pathways adaptation supports acquisition of activated microglia phenotype.J. Neurosci. Res. 2014; 92: 723-731Crossref PubMed Scopus (106) Google Scholar,32.Nair S. et al.Lipopolysaccharide-induced alteration of mitochondrial morphology induces a metabolic shift in microglia modulating the inflammatory response in vitro and in vivo.Glia. 2019; 67: 1047-1061Crossref PubMed Scopus (68) Google Scholar], but are also capable of importing it from the extracellular space. For lactate to be imported and metabolized, recipient cells need to be equipped with transporters and enzymes that allow efficient oxidation. Lactate transport across cell membranes is made possible by the presence of monocarboxylate transporters (MCTs). Among these, MCT1, MCT2, and MCT4 – encoded by the genes Slc16a1, Slc16a7, and Slc16a3, respectively – are the most abundant in the brain and are all capable of shuttling lactate, pyruvate, and ketone bodies, although with different affinities [33.Halestrap A.P. The SLC16 gene family – structure, role and regulation in health and disease.Mol. Asp. Med. 2013; 34: 337-349Crossref PubMed Scopus (357) Google Scholar]. The directionality of lactate transport depends on the concentration gradient as well as on the presence of protons because these proteins act as lactate/proton symporters. Each transporter exhibits a specific cellular distribution, and the literature reports that MCT1 is expressed mostly by endothelial cells, ependymocytes, and astrocytes, MCT4 is expressed by astrocytes, whereas MCT2 is found almost exclusively in neurons [23.Pellerin L. et al.Expression of monocarboxylate transporter mRNAs in mouse brain: support for a distinct role of lactate as an energy substrate for the neonatal vs. adult brain.Proc. Natl. Acad. Sci. U. S. A. 1998; 95: 3990-3995Crossref PubMed Scopus (240) Google Scholar]. MCT expression can vary according to the developmental stage of the individual as well as in pathological states. Do microglia express MCTs? Although not extensively investigated, it has been recently reported that microglia do express MCTs [34.Ding F. et al.Early decline in glucose transport and metabolism precedes shift to ketogenic system in female aging and Alzheimer's mouse brain: implication for bioenergetic intervention.PLoS One. 2013; 8e79977Crossref PubMed Scopus (148) Google Scholar, 35.Nijland P.G. et al.Cellular distribution of glucose and monocarboxylate transporters in human brain white matter and multiple sclerosis lesions.Glia. 2014; 62: 1125-1141Crossref PubMed Scopus (65) Google Scholar, 36.Kong L. et al.Monocarboxylate transporter 1 promotes classical microglial activation and pro-inflammatory effect via 6-phosphofructo-2-kinase/fructose-2, 6-biphosphatase 3.J. Neuroinflammation. 2019; 16: 240Crossref PubMed Scopus (20) Google Scholar, 37.Moreira T.J. et al.Enhanced cerebral expression of MCT1 and MCT2 in a rat ischemia model occurs in activated microglial cells.J. Cereb. 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In addition to the presence of suitable transporters, lactate oxidation is tightly dependent on the expression of the enzyme lactate dehydrogenase (LDH) which catalyzes the reversible conversion of pyruvate and NADH to lactate and NAD+ in a dynamic equilibrium [39.Rogatzki M.J. et al.Lactate is always the end product of glycolysis.Front. Neurosci. 2015; 9: 22Crossref PubMed Scopus (162) Google Scholar]. This enzyme is found either as a homotetramers or a heterotetramers of two different subunits (LDHA and LDHB). LDHB is mostly responsible for catabolizing lactate into pyruvate, whereas the opposite is true for LDHA [39.Rogatzki M.J. et al.Lactate is always the end product of glycolysis.Front. Neurosci. 2015; 9: 22Crossref PubMed Scopus (162) Google Scholar,40.Urbańska K. Orzechowski A. Unappreciated role of LDHA and LDHB to control apoptosis and autophagy in tumor cells.Int. J. Mol. Sci. 2019; 20: 2085Crossref Scopus (62) Google Scholar]. Therefore, the differential composition of the LDH tetramer can also contribute, together with other factors, to shifting the reaction towards lactate catabolism or production. Interestingly, the expression of Ldhb peaks in microglia in early postnatal brain (~2 weeks of age), a period characterized by high microglia-dependent synaptic remodeling. By contrast, the expression of Ldha is minimal at this timepoint [41.Bennett M.L. et al.New tools for studying microglia in the mouse and human CNS.Proc. Natl. Acad. Sci. U. S. A. 2016; 113: E1738-E1746Crossref PubMed Scopus (887) Google Scholar], suggesting that lactate oxidation, rather than production, takes place in microglia during this developmental window. Consistent with a role for lactate during the perinatal period, a higher concentration of this metabolite has been reported in human neonatal brain compared with the brains of infants and children [42.Tomiyasu M. et al.Normal lactate concentration range in the neonatal brain.Magn. Reson. Imaging. 2016; 34: 1269-1273Crossref PubMed Scopus (8) Google Scholar]. Of note, we and others reported that ldhb is among the most abundant genes expressed in microglia, and that its expression levels are considerably higher than in macrophages in other tissues (ArrayExpress database: E-MEXP-3347 [8.Pinto A.R. et al.An abundant tissue macrophage population in the adult murine heart with a distinct alternatively-activated macrophage profile.PLoS One. 2012; 7e36814Crossref PubMed Scopus (205) Google Scholar,9.Zhang Y. et al.An RNA-sequencing transcriptome and splicing database of glia, neurons, and vascular cells of the cerebral cortex.J. Neurosci. 2014; 34: 11929-11947Crossref PubMed Scopus (2637) Google Scholar]). Furthermore, at least in the adult hippocampus, ldhb is almost exclusively microglia-specific in comparison to other cell types (Figure 1) [43.Mattei D. et al.Enzymatic dissociation induces transcriptional and proteotype bias in brain cell populations.Int. J. Mol. Sci. 2020; 21: 7944Crossref PubMed Scopus (26) Google Scholar]. Together, this evidence indicates that lactate may be imported into microglia, promptly oxidized to pyruvate by LDHB, and thus used as a bioenergetic substrate to fuel the tricarboxylic acid (TCA) cycle, supporting a critical role for microglial lactate metabolism. Of note, a recent study conducted on the immortalized murine microglial cell line BV-2 also showed that lactate positively modulates several key microglia features, including proliferation, migration, and phagocytosis [31.Liu Y. et al.Functions of lactate in the brain of rat with intracerebral hemorrhage evaluated with MRI/MRS and in vitro approaches.CNS Neurosci. Ther. 2020; 26: 1031-1044Crossref PubMed Scopus (9) Google Scholar]. Although microglia appear to have all the elements required to efficiently metabolize lactate, further in vivo studies will be necessary to confirm a role of lactate in controlling microglial function. In addition, given the heterogeneity of microglia in the CNS, it will be important to investigate whether regional differences might influence microglial lactate metabolism. The effects of lactate on microglia have been poorly investigated, and no studies are available, to the best of our knowledge, that directly address the role of lactate in modulating microglial function in vivo. However, more is known about the role of this metabolite in other macrophages. Tissue-resident macrophages play important roles in homeostasis and serve as sentinels for tissue damage and foreign antigens. The local environment in which macrophages reside dictates relevant differences in gene expression, and also in morphological, antigenic, and functional properties [44.Gordon S. Taylor P.R. Monocyte and macrophage heterogeneity.Nat. Rev. Immunol. 2005; 5: 953-964Crossref PubMed Scopus (3674) Google Scholar]. Although intrinsic and context-dependent differences emerge in microglia compared with other tissue-resident macrophages, thus limiting direct comparison, these cells share many commonalities. Therefore, some of the functions described for lactate in peripheral macrophages could be at least partially translated to microglia. One of the best-characterized contexts in which the effects of lactate on immune cells have been studied is the tumor microenvironment. Lactate accumulates massively in the tumor milieu because of the preferential glycolytic metabolism adopted by cancer cells. In this environment it acts synergistically with other tumor-derived factors to reprogram surrounding immune cells to an immune-tolerant phenotype, ultimately favoring tumor growth [45.Certo M. et al.Lactate modulation of immune responses in inflammatory versus tumour microenvironments.Nat. Rev. Immunol. 2021; 21: 151-161Crossref PubMed Scopus (64) Google Scholar]. Tumor-associated macrophages (TAMs) sense lactate through various routes, including the activation of transmembrane receptors as well as through direct lactate import. In these cells, lactate induces the expression of several genes that are linked to anti-inflammatory and tissue-repair associated phenotypes [46.Colegio O.R. et al.Functional polarization of tumour-associated macrophages by tumour-derived lactic acid.Nature. 2014; 513: 559-563Crossref PubMed Scopus (1283) Google Scholar]. In the brain, glioblastoma microglia exhibit profound transcriptional changes, characterized by a downregulated homeostatic transforming growth factor (TGF)-β pathway and downregulation of their sensing capacity, whereas genes involved in phagocytic activity are upregulated [47.Maas S.L.N. et al.Glioblastoma hijacks microglial gene expression to support tumor growth.J. Neuroinflammation. 2020; 17: 120Crossref PubMed Scopus (31) Google Scholar]. In vitro experiments show that glioma cells have a rate of glucose consumption – fourfold higher than microglia [48.Voisin P. et al.Microglia in close vicinity of glioma cells: correlation between phenotype and metabolic alterations.Front. Neuroenerg. 2010; 2: 131Crossref PubMed Google Scholar] – and abundantly release lactate. Whether the lactate released by glioma cells instructs microglia in vivo, as it does for TAMs, remains to be further confirmed. Moreover, with regard to metabolic flexibility, cancer cells themselves may also be very instructive because they are characterized by high metabolic plasticity and, depending on their availability, can rapidly adapt to diverse energetic substrates – including glucose, glutamine, lactate, and lipids (reviewed in [49.Lehuédé C. et al.Metabolic plasticity as a determinant of tumor growth and metastasis.Cancer Res. 2016; 76: 5201-5208Crossref PubMed Scopus (158) Google Scholar]). As a convincing example, oxidative cancer cells utilize lactate provided by glycolytic cancer cells, thus sparing glucose and optimizing its bioavailability for hypoxic cells [50.Sonveaux P. et al.Targeting lactate-fueled respiration selectively kills hypoxic tumor cells in mice.J. Clin. Invest. 2008; 118: 3930-3942PubMed Google Scholar,51.Kennedy K.M. et al.Catabolism of exogenous lactate reveals it as a legitimate metabolic substrate in breast cancer.PLoS One. 2013; 8e75154Crossref PubMed Scopus (119) Google Scholar]. The term 'metabolic symbiosis' was in fact coined to describe the adaptation of some cancer cells to the preferential use of lactate as an energy substrate. Interestingly, in oxidative cancer cells, lactate is not only imported as an alternative energy source but is also utilized to promote v-ATPase-dependent lysosomal acidification and autophagy via LDHB activity [52.Brisson L. et al.Lactate dehydrogenase B controls lysosome activity and autophagy in cancer.Cancer Cell. 2016; 30: 418-431Abstract Full Text Full Text PDF PubMed Scopus (101) Google Scholar]. This is indeed a critical process that occurs during the oxidation to pyruvate because the protons produced in the reaction are readily used by the v-ATPase pumps that are located in proximity to the LDHB complexes [52.Brisson L. et al.Lactate dehydrogenase B controls lysosome activity and autophagy in cancer.Cancer Cell. 2016; 30: 418-431Abstract Full Text Full Text PDF PubMed Scopus (101) Google Scholar]. Microglia, the major phagocytes of the brain, heavily rely on their degradation machinery, and lysosomes are thus of utmost importance for the execution of basic microglial tasks. It is therefore tempting to speculate that – similarly to oxidative cancer cells – microglia could import extracellular lactate to enhance the acidification of their lysosomes and thus ensure their homeostatic functions in the brain. In specific situations, local lactate metabolism can be highly relevant in the adult brain. One such example is during experience-dependent memory formation. Hippocampal lactate, released from astrocytes, is emerging as an important regulator of learning and memory, at least in hippocampus-dependent tasks [53.Suzuki A. et al.Astrocyte–neuron lactate transport is required for long-term memory formation.Cell. 2011; 144: 810-823Abstract Full Text Full Text PDF PubMed Scopus (927) Google Scholar, 54.Newman L.A. et al.Lactate produced by glycogenolysis in astrocytes regulates memory processing.PLoS One. 2011; 6e28427Crossref PubMed Scopus (297) Google Scholar, 55.Korol D.L. et al.Involvement of lactate transport in two object recognition tasks that require either the hippocampus or striatum.Behav. Neurosci. 2019; 133: 176-187Crossref PubMed Scopus (12) Google Scholar, 56.Descalzi G. et al.Lactate from astrocytes fuels learning-induced mRNA translation in excitatory and inhibitory neurons.Commun Biol. 2019; 2: 247Crossref PubMed Scopus (55) Google Scholar]. 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Several studies have reported a crucial involvement of microglia in both these forms of synaptic plasticity [58.Paolicelli R.C. et al.Synaptic pruning by microglia is necessary for normal brain development.Science. 2011