Microglia lactylation in relation to central nervous system diseases

The development of neurodegenerative diseases is closely related to the disruption of central nervous system homeostasis. Microglia, as innate immune cells, play important roles in the maintenance of central nervous system homeostasis, injury response, and neurodegenerative diseases. Lactate has been considered a metabolic waste product, but recent studies are revealing ever more of the physiological functions of lactate. Lactylation is an important pathway in lactate function and is involved in glycolysis-related functions, macrophage polarization, neuromodulation, and angiogenesis and has also been implicated in the development of various diseases. This review provides an overview of the lactate metabolic and homeostatic regulatory processes involved in microglia lactylation, histone versus non-histone lactylation, and therapeutic approaches targeting lactate. Finally, we summarize the current research on microglia lactylation in central nervous system diseases. A deeper understanding of the metabolic regulatory mechanisms of microglia lactylation will provide more options for the treatment of central nervous system diseases.

[1]  Yanhui Cai,et al.  Lactate: a prospective target for therapeutic intervention in psychiatric disease , 2023, Neural regeneration research.

[2]  Anran Huo,et al.  Molecular mechanisms underlying microglial sensing and phagocytosis in synaptic pruning , 2023, Neural regeneration research.

[3]  S. Qiu,et al.  Lactylome analysis suggests lactylation-dependent mechanisms of metabolic adaptation in hepatocellular carcinoma , 2023, Nature Metabolism.

[4]  Xueli Song,et al.  Netrin-4: Focus on Its Role in Axon Guidance, Tissue Stability, Angiogenesis and Tumors , 2022, Cellular and Molecular Neurobiology.

[5]  Huakun Wang,et al.  The heterogeneity of microglial activation and its epigenetic and non-coding RNA regulations in the immunopathogenesis of neurodegenerative diseases , 2022, Cellular and Molecular Life Sciences.

[6]  R. Parenti,et al.  Lactate modulates microglia polarization via IGFBP6 expression and remodels tumor microenvironment in glioblastoma , 2022, Cancer Immunology, Immunotherapy.

[7]  Won-Jae Kim,et al.  Epigallocatechin Gallate Protects against Hypoxia-Induced Inflammation in Microglia via NF-κB Suppression and Nrf-2/HO-1 Activation , 2022, International journal of molecular sciences.

[8]  Hao Wang,et al.  Lactylation-driven METTL3-mediated RNA m6A modification promotes immunosuppression of tumor-infiltrating myeloid cells. , 2022, Molecular cell.

[9]  Lijia Chang,et al.  (R)-ketamine ameliorates demyelination and facilitates remyelination in cuprizone-treated mice: A role of gut–microbiota–brain axis , 2022, Neurobiology of Disease.

[10]  Bangmao Wang,et al.  Lactic Acid-Producing Probiotic Saccharomyces cerevisiae Attenuates Ulcerative Colitis via Suppressing Macrophage Pyroptosis and Modulating Gut Microbiota , 2021, Frontiers in Immunology.

[11]  A. Drzezga,et al.  Microglial activation states drive glucose uptake and FDG-PET alterations in neurodegenerative diseases , 2021, Science Translational Medicine.

[12]  Xiaotang Wang,et al.  YY1 lactylation in microglia promotes angiogenesis through transcription activation-mediated upregulation of FGF2 , 2021, Genome Biology.

[13]  Kangdong Liu,et al.  FSL-Kla: A few-shot learning-based multi-feature hybrid system for lactylation site prediction , 2021, Computational and structural biotechnology journal.

[14]  David L. Williams,et al.  Lactate promotes macrophage HMGB1 lactylation, acetylation, and exosomal release in polymicrobial sepsis , 2021, Cell death and differentiation.

[15]  Xiaoxi Meng,et al.  Comprehensive Analysis of Lysine Lactylation in Rice (Oryza sativa) Grains. , 2021, Journal of agricultural and food chemistry.

[16]  V. Mahan.  Effects of lactate and carbon monoxide interactions on neuroprotection and neuropreservation , 2021, Medical gas research.

[17]  Jun Shi,et al.  Lactylation, a Novel Metabolic Reprogramming Code: Current Status and Prospects , 2021, Frontiers in Immunology.

[18]  Li Sun,et al.  Lactate Modulates Cellular Metabolism Through Histone Lactylation-Mediated Gene Expression in Non-Small Cell Lung Cancer , 2021, Frontiers in Oncology.

[19]  Yingming Zhao,et al.  Class I histone deacetylases (HDAC1–3) are histone lysine delactylases , 2021, bioRxiv.

[20]  Xianqun Fan,et al.  Histone lactylation drives oncogenesis by facilitating m6A reader protein YTHDF2 expression in ocular melanoma , 2021, Genome biology.

[21]  G. Kempermann,et al.  L-lactate exerts a pro-proliferative effect on adult hippocampal precursor cells in vitro , 2021, iScience.

[22]  H. Shoji,et al.  Protein lactylation induced by neural excitation , 2021, bioRxiv.

[23]  S. Koh,et al.  Neuroinflammation in neurodegenerative disorders: the roles of microglia and astrocytes , 2020, Translational Neurodegeneration.

[24]  Viral G. Jain,et al.  TLR signaling adapter BCAP regulates inflammatory to reparatory macrophage transition by promoting histone lactylation , 2020, Proceedings of the National Academy of Sciences.

[25]  W. Liang,et al.  Systematic Analysis of Lysine Lactylation in the Plant Fungal Pathogen Botrytis cinerea , 2020, Frontiers in Microbiology.

[26]  David L. Williams,et al.  Lactate Suppresses Macrophage Pro-Inflammatory Response to LPS Stimulation by Inhibition of YAP and NF-κB Activation via GPR81-Mediated Signaling , 2020, Frontiers in Immunology.

[27]  B. MacVicar,et al.  Immunometabolism in the Brain: How Metabolism Shapes Microglial Function , 2020, Trends in Neurosciences.

[28]  Erika L. Varner,et al.  Quantification of lactoyl-CoA (lactyl-CoA) by liquid chromatography mass spectrometry in mammalian cells and tissues , 2020, Open Biology.

[29]  J. Storm-Mathisen,et al.  The Lactate Receptor HCA1 Is Present in the Choroid Plexus, the Tela Choroidea, and the Neuroepithelial Lining of the Dorsal Part of the Third Ventricle , 2020, International journal of molecular sciences.

[30]  Ping-Chih Ho,et al.  Lactate modulation of immune responses in inflammatory versus tumour microenvironments , 2020, Nature Reviews Immunology.

[31]  Ting Li,et al.  Microglia induce the transformation of A1/A2 reactive astrocytes via the CXCR7/PI3K/Akt pathway in chronic post-surgical pain , 2020, Journal of Neuroinflammation.

[32]  Yue Wang,et al.  Modulation of the Astrocyte-Neuron Lactate Shuttle System contributes to Neuroprotective action of Fibroblast Growth Factor 21 , 2020, Theranostics.

[33]  Steffen Jung,et al.  Novel Hexb-based tools for studying microglia in the CNS , 2020, Nature Immunology.

[34]  M. Kreutz,et al.  The immunological Warburg effect: Can a metabolic‐tumor‐stroma score (MeTS) guide cancer immunotherapy? , 2020, Immunological reviews.

[35]  M. Morris,et al.  Monocarboxylate Transporters (SLC16): Function, Regulation, and Role in Health and Disease , 2020, Pharmacological Reviews.

[36]  E. Pålsson-McDermott,et al.  Targeting immunometabolism as an anti-inflammatory strategy , 2020, Cell Research.

[37]  Bin Zhang,et al.  Microglia and macrophages promote corralling, wound compaction and recovery after spinal cord injury via Plexin-B2 , 2020, Nature Neuroscience.

[38]  Christine Grienberger,et al.  Synaptic Plasticity Forms and Functions. , 2020, Annual review of neuroscience.

[39]  Yue Hu,et al.  PI3K-Akt-mTOR/PFKFB3 pathway mediated lung fibroblast aerobic glycolysis and collagen synthesis in lipopolysaccharide-induced pulmonary fibrosis , 2020, Laboratory Investigation.

[40]  S. David,et al.  Immune cell regulation of glia during CNS injury and disease , 2020, Nature Reviews Neuroscience.

[41]  G. Brooks.  Lactate as a fulcrum of metabolism , 2020, Redox biology.

[42]  J. Locasale,et al.  Histone Lactylation: A New Role for Glucose Metabolism. , 2019, Trends in biochemical sciences.

[43]  Valentina Scandella,et al.  Sensing the Environment: Extracellular Lactate Levels Control Adult Neurogenesis. , 2019, Cell stem cell.

[44]  Zehua Wang,et al.  Monocarboxylate transporter 1 promotes classical microglial activation and pro-inflammatory effect via 6-phosphofructo-2-kinase/fructose-2, 6-biphosphatase 3 , 2019, Journal of Neuroinflammation.

[45]  James R. Roede,et al.  Non-enzymatic Lysine Lactoylation of Glycolytic Enzymes. , 2019, Cell chemical biology.

[46]  A. Galaz,et al.  Monocarboxylate transporter 4 (MCT4) is a high affinity transporter capable of exporting lactate in high-lactate microenvironments , 2019, The Journal of Biological Chemistry.

[47]  Huanming Yang,et al.  Brain Endothelial Cells Maintain Lactate Homeostasis and Control Adult Hippocampal Neurogenesis. , 2019, Cell stem cell.

[48]  Helmut Kettenmann,et al.  Cien Años de Microglía: Milestones in a Century of Microglial Research , 2019, Trends in Neurosciences.

[49]  Steffen Jung,et al.  Microglia Biology: One Century of Evolving Concepts , 2019, Cell.

[50]  B. Ren,et al.  Metabolic regulation of gene expression by histone lactylation , 2019, Nature.

[51]  Sung Hoon Baik,et al.  A Breakdown in Metabolic Reprogramming Causes Microglia Dysfunction in Alzheimer's Disease. , 2019, Cell metabolism.

[52]  M. Drutskaya,et al.  [The Role of Microglia in the Homeostasis of the Central Nervous System and Neuroinflammation]. , 2019, Molekuliarnaia biologiia.

[53]  Baohui Xu,et al.  Significance and Mechanisms of P-glycoprotein in Central Nervous System Diseases. , 2019, Current drug targets.

[54]  J. Meier,et al.  Epigenetic regulation by endogenous metabolite pharmacology. , 2019, Current opinion in chemical biology.

[55]  C. Alberini,et al.  Lactate from astrocytes fuels learning-induced mRNA translation in excitatory and inhibitory neurons , 2019, Communications Biology.

[56]  J. Rabinowitz,et al.  The Tumor Metabolic Microenvironment: Lessons from Lactate. , 2019, Cancer research.

[57]  Junbo Hu,et al.  Lactate Is a Natural Suppressor of RLR Signaling by Targeting MAVS , 2019, Cell.

[58]  Qingsong Liu,et al.  Sodium rutin ameliorates Alzheimer’s disease–like pathology by enhancing microglial amyloid-β clearance , 2019, Science Advances.

[59]  S. Datta,et al.  Age related rise in lactate and its correlation with lactate dehydrogenase (LDH) status in post-mitochondrial fractions isolated from different regions of brain in mice , 2018, Neurochemistry International.

[60]  P. Oefner,et al.  Double genetic disruption of lactate dehydrogenases A and B is required to ablate the “Warburg effect” restricting tumor growth to oxidative metabolism , 2018, The Journal of Biological Chemistry.

[61]  Joseph R. Scarpa,et al.  Epigenetic regulation of brain region-specific microglia clearance activity , 2018, Nature Neuroscience.

[62]  G. Brooks.  The Science and Translation of Lactate Shuttle Theory. , 2018, Cell metabolism.

[63]  Pierre J. Magistretti,et al.  Lactate in the brain: from metabolic end-product to signalling molecule , 2018, Nature Reviews Neuroscience.

[64]  B. Weber,et al.  CrossTalk proposal: an important astrocyte‐to‐neuron lactate shuttle couples neuronal activity to glucose utilisation in the brain , 2018, The Journal of physiology.

[65]  N. Secher,et al.  Maintained exercise‐enhanced brain executive function related to cerebral lactate metabolism in men , 2017, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[66]  Beth Stevens,et al.  Microglia emerge as central players in brain disease , 2017, Nature Medicine.

[67]  Luyong Zhang,et al.  Microglia: Housekeeper of the Central Nervous System , 2017, Cellular and Molecular Neurobiology.

[68]  D. Rowitch,et al.  Neurotoxic reactive astrocytes are induced by activated microglia , 2017, Nature.

[69]  Matthew T. Maurano,et al.  Genetic Drivers of Epigenetic and Transcriptional Variation in Human Immune Cells , 2016, Cell.

[70]  S. Haferkamp,et al.  LDHA-Associated Lactic Acid Production Blunts Tumor Immunosurveillance by T and NK Cells. , 2016, Cell metabolism.

[71]  Masaki Kobayashi,et al.  Effect of diclofenac on SLC16A3/MCT4 by the Caco-2 cell line. , 2016, Drug metabolism and pharmacokinetics.

[72]  A. Louveau,et al.  Targeting the CD80/CD86 costimulatory pathway with CTLA4‐Ig directs microglia toward a repair phenotype and promotes axonal outgrowth , 2015, Glia.

[73]  Yingming Zhao,et al.  The rate of glycolysis quantitatively mediates specific histone acetylation sites , 2015, Cancer & metabolism.

[74]  Maja A. Puchades,et al.  The lactate receptor, G‐protein‐coupled receptor 81/hydroxycarboxylic acid receptor 1: Expression and action in brain , 2015, Journal of neuroscience research.

[75]  L. Bergersen.  Lactate Transport and Signaling in the Brain: Potential Therapeutic Targets and Roles in Body—Brain Interaction , 2015, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[76]  W. Le,et al.  Differential Roles of M1 and M2 Microglia in Neurodegenerative Diseases , 2015, Molecular Neurobiology.

[77]  Albert Gjedde,et al.  Lactate receptor sites link neurotransmission, neurovascular coupling, and brain energy metabolism. , 2014, Cerebral cortex.

[78]  T. Maniatis,et al.  An RNA-Sequencing Transcriptome and Splicing Database of Glia, Neurons, and Vascular Cells of the Cerebral Cortex , 2014, The Journal of Neuroscience.

[79]  R. Brinton,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 , 2013, PloS one.

[80]  M. Graeber,et al.  The molecular profile of microglia under the influence of glioma. , 2012, Neuro-oncology.

[81]  V. Préat,et al.  Lactate stimulates angiogenesis and accelerates the healing of superficial and ischemic wounds in mice , 2012, Angiogenesis.

[82]  Alberto Mantovani,et al.  Macrophage plasticity and polarization: in vivo veritas. , 2012, The Journal of clinical investigation.

[83]  A. Halestrap.  The monocarboxylate transporter family—Structure and functional characterization , 2012, IUBMB life.

[84]  F. Végran,et al.  Lactate influx through the endothelial cell monocarboxylate transporter MCT1 supports an NF-κB/IL-8 pathway that drives tumor angiogenesis. , 2011, Cancer research.

[85]  Sarah A. Stern,et al.  Astrocyte-Neuron Lactate Transport Is Required for Long-Term Memory Formation , 2011, Cell.

[86]  S. Moncada,et al.  Glycolysis: a bioenergetic or a survival pathway? , 2010, Trends in biochemical sciences.

[87]  N. Secher,et al.  Blood Lactate is an Important Energy Source for the Human Brain , 2009, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[88]  A. Schurr.  Lactate: a major and crucial player in normal function of both muscle and brain , 2008, The Journal of physiology.

[89]  Gregor Rothe,et al.  Inhibitory effect of tumor cell-derived lactic acid on human T cells. , 2007, Blood.

[90]  A. Mackensen,et al.  Tumor-derived lactic acid modulates dendritic cell activation and antigen expression. , 2006, Blood.

[91]  Peter A. Jones,et al.  Epigenetics in human disease and prospects for epigenetic therapy , 2004, Nature.

[92]  M. Tseng,et al.  Blockade of lactate transport exacerbates delayed neuronal damage in a rat model of cerebral ischemia , 2001, Brain Research.

[93]  P. Magistretti,et al.  Selective Distribution of Lactate Dehydrogenase Isoenzymes in Neurons and Astrocytes of Human Brain , 1996, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[94]  J. Pouysségur,et al.  Genetic disruption of lactate/H+ symporters (MCTs) and their subunit CD147/BASIGIN sensitizes glycolytic tumor cells to phenformin. , 2015, Cancer research.