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The immunologic Warburg effect: Evidence and therapeutic opportunities in autoimmunity

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Abstract Pro‐inflammatory signals induce metabolic reprogramming in innate and adaptive immune cells of both myeloid and lymphoid lineage, characterized by a shift to aerobic glycolysis akin to the Warburg effect first described in cancer. Blocking the switch to aerobic glycolysis impairs the survival, differentiation, and effector functions of pro‐inflammatory cell types while favoring anti‐inflammatory and regulatory phenotypes. Glycolytic reprogramming may therefore represent a selective vulnerability of inflammatory immune cells, providing an opportunity to modulate immune responses in autoimmune disease without broad toxicity in other tissues of the body. The mechanisms by which aerobic glycolysis and the balance between glycolysis and oxidative phosphorylation regulate immune responses have only begun to be understood, with many additional insights expected in the years to come. Immunometabolic therapies targeting aerobic glycolysis include both pharmacologic inhibitors of key enzymes and glucose‐restricted diets, such as the ketogenic diet. Animal studies support a role for these pharmacologic and dietary therapies for the treatment of autoimmune diseases, and in a few cases proof of concept has been demonstrated in human disease. Nonetheless, much more work is needed to establish the clinical safety and efficacy of these treatments. This article is categorized under: Biological Mechanisms > Metabolism Translational, Genomic, and Systems Medicine > Translational Medicine Biological Mechanisms > Cell Signaling
Glycolytic reprogramming is conserved among inflammatory immune subsets. Glycolytic upregulation, including the increased lactate production in the presence of oxygen that defines aerobic glycolysis, occurs following inflammatory activation of cells from both myeloid and lymphoid lineage. In contrast, regulatory and/or anti‐inflammatory immune subsets generally rely on oxidative energy metabolism. Inhibiting glycolysis through genetic or pharmacologic measures prevents inflammatory immune activation, including the differentiation and effector functions of inflammatory cells, while promoting differentiation of regulatory subsets. 2‐DG, 2‐deoxy‐d‐glucose
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Aerobic glycolysis in immune activation: Mechanisms and pharmacologic targets. The mechanisms by which aerobic glycolysis regulates inflammatory immune functions are still being elucidated. Several currently described transcriptional and posttranscriptional mechanisms of immune regulation are depicted above. Glycolysis‐related metabolites that directly modify proteins are shown in blue. A number of pharmacologic inhibitors of glycolytic enzymes and associated proteins have demonstrated efficacy without toxicity in animal models of autoimmunity or human autoimmune disease. Some examples are shown here, boxed in red. 2‐DG, 2‐deoxy‐d‐glucose; 3‐BP, 3‐bromopyruvate; 4‐OI, 4‐octyl itaconate; DMF, dimethyl fumarate. HA, heptelidic acid; LGSH, lactoylglutathione; MGO, methylglyoxal
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Biological Mechanisms > Cell Signaling
Translational, Genomic, and Systems Medicine > Translational Medicine
Biological Mechanisms > Metabolism

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