Glucose transporter 1 in rheumatoid arthritis and autoimmunity

Advanced Review

Ekaterina Zezina, Oezen Sercan‐Alp, Matthias Herrmann, Nadine Biesemann

Published Online: Feb 21 2020

DOI: 10.1002/wsbm.1483

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Abstract Knowledge about metabolism of immune cells increased almost exponentially during the last two decades and thereby created the new area immunometabolism. Increased glucose uptake and glycolysis were identified as one of the major drivers in immune cells for rapid adaptation to changes in the microenvironment or external stimuli. These metabolic switches are crucial to generate macromolecules for immune cell proliferation and activation. Glucose transporter 1 (GLUT1), a ubiquitously expressed glucose transporter, is strongly upregulated after innate and adaptive immune cell activation. Deletion or inhibition of GLUT1 blocked T cell proliferation and effector function, antibody production from B cells and reduced inflammatory responses in macrophages. Increased glucose uptake and GLUT1 expression are not only observed in proinflammatory conditions, but also in murine models of autoimmunity as well as in human patients. Rheumatoid arthritis (RA), the most common autoimmune disease, is characterized by infiltration of immune cells, hyperproliferation of fibroblast‐like synoviocytes, and destruction of cartilage and bone. These processes create a hypoxic microenvironment in the synovium. Moreover, synovial samples including fibroblast‐like synoviocytes from RA patients showed increased lactate level and upregulate GLUT1. Similar upregulation of GLUT1 is observed in systemic lupus erythematosus and psoriasis patients as well as in murine autoimmune models. Inhibition of GLUT1 using either T cell specific knockouts or small molecule GLUT1/glycolysis inhibitors improved phenotypes of different murine autoimmune disease models like arthritis, lupus, and psoriasis. Thereby the therapeutic potential of immunometabolism and especially interference with glycolysis was proven. This article is categorized under: Biological Mechanisms > Metabolism Translational, Genomic, and Systems Medicine > Translational Medicine Physiology > Mammalian Physiology in Health and Disease

Simplified scheme of glycolysis and described inhibitors. Glucose uptake is regulated via the GLUT (SLC2A) family of glucose transporters. Glucose is then catalyzed to glucose‐6‐phosphate by hexokinase, one of the rate limiting enzymes in glycolysis. Glucose‐6‐phosphate feeds either into the pentose phosphate pathway to generate precursors for nucleotides and amino acids or into glycolysis. The second rate limiting enzyme in glycolysis is phosphofructokinase (PFK), which is allosterically regulated by fructose‐2,6 bisphosphate and AMP. Fructose‐2,6 bisphosphate is generated by PFKFB3. During glycolysis several enzymatic reactions convert glucose‐6‐phosphate to pyruvate. Pyruvate can then be either transformed to lactate and exported from the cell or transported to mitochondria where it is incorporated into the TCA cycle. The TCA cycle generates precursors for amino acids as well as NADH and FADH₂. These reducing agents as well as succinate from TCA cycle are essential to support oxidative phosphorylation and thereby generate the majority of ATP. The inhibitors that are mentioned in the review are depictured in black in front of enzymes. Several reviews have already described more advanced glycolysis inhibitors in tumor cells, because glycolysis suppression is considered as cancer treatment (Akins, Nielson, & Le, ; Granchi, Fortunato, & Minutolo, ). 1,3‐BPG, 1,3‐bisphosphoglycerate; 2‐DG, 2‐deoxyglucose; 2‐PG, 2‐phosphoglycerate; 3‐BP, 3‐bromopyruvate; 3‐PG, 3‐phosphoglycerate; 3‐PO, 3‐(3‐pyridinyl)‐1‐(4‐pyridinyl)‐2‐propen‐1‐one; ALD, aldolase; ENO, enolase; F‐1,6‐bisP, fructose 1,6‐bisphosphate; F‐2,6‐bisP, fructose 2,6‐bisphosphate; F6P, fructose 6‐phosphate; G6P, glucose 6‐phosphate; G6PD, glucose‐6‐phosphate dehydrogenase; GA‐3‐P, glyceraldehyde 3‐phopate; GAPDH, glyceraldehyde‐3‐phosphate dehydrogenase; GLUT, glucose transporter; GPI, glucose‐6‐phosphate isomerase; HK, hexokinase; LDH, lactate dehydrogenase; MCT, monocarboxylate transporter; PEP, phosphoenolpyruvic acid; PFK, phosphofructokinase; PFKFB3, 6‐phosphofructo‐2‐kinase/fructose‐2,6‐biphosphatase 3; PGAM1, phosphoglycerate mutase 1; PGK, phosphoglycerate kinase; PKM, pyruvate kinase M; TCA cycle, tricarboxylic acid cycle

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