The immunologic Warburg effect: Evidence and therapeutic opportunities in autoimmunity

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

Identification of Metabolic Biomarkers in Relation to Methotrexate Response in Early Rheumatoid Arthritis

“…Especially the Warburg effect, describing a shift towards inefficient energy production through aerobic glycolysis, and well recognized for its impact on drug response in cancer cells [ 44 ], has been extensively described in RA patients, as well as the upregulation of glycolysis [ 45 , 46 , 47 , 48 , 49 ]. As these processes have been associated with a proinflammatory state, targeting the Warburg effect or glycolysis has been suggested as a potential RA therapy [ 50 , 51 , 52 , 53 ]. However, these processes have, to date, not been linked to the response to existing therapies in RA.…”

Exploring the Proteomic Alterations from Untreated and Cryoablation and Irradiation Treated Giant Cell Tumors of Bone Using Liquid-Chromatography Tandem Mass Spectrometry

“…In addition to these, most of the key enzymes that play an essential role in glycolysis and molecular cell-signaling showed remarkably down-regulated expressions in GCT-untreated/control, indicating glycolysis has been critically affected due to the aggressive nature of the tumor. It has been hypothesized that cancer cells quickly adapt to a mechanism that provides biosynthetic requirements for the rapid proliferation of cells causing alterations of glycolytic enzymes [ 31 ]. Hence, the identified dysregulated protein expressions indicate that there could be a Warburg effect that occurred inside the tumor cells.…”

Ketogenic Diet as a Preventive and Supportive Care for COVID-19 Patients

“…KDs inhibit aerobic glycolysis, which has been proven to occur following inflammatory activation of cells from both myeloid and lymphoid lineage; in particular, KDs prevent the differentiation and effector functions of inflammatory cells, while promoting the differentiation of regulatory subsets. Moreover, the ketone body β- hydroxybutyrate blocks NLRP3 inflammasome activation [ 20 ].…”

“…VLCKDs are currently used in bariatric surgery preparation [ 12 ] thanks to the ability in reducing hepatic volume [ 11 ] with a subsequent improvement in intra and post-operative care. Recent findings underlined immune advantages derived from ketone bodies, such as blockage NLRP3 inflammasome [ 20 ], reduction in chronic activation of ILCs and induction of protective γδ T-cells against infections [ 10 ]. Taken together, in addition to the benefit of airway inflammation prevention by impairing the formation of lipid droplets [ 22 ], KDs could be an excellent tool to prevent the infection and stem the damage induced by COVID-19 in the fragile population affected from obesity.…”