2-Deoxy-d-Glucose Treatment Decreases Anti-inflammatory M2 Macrophage Polarization in Mice with Tumor and Allergic Airway Inflammation

Abstract

As important effector cells in inflammation, macrophages can be functionally polarized into either inflammatory M1 or alternatively activated anti-inflammatory M2 phenotype depending on surroundings. The key roles of glycolysis in M1 macrophage polarization have been well defined. However, the relationship between glycolysis and M2 polarized macrophages is still poorly understood. Here, we report that 2-deoxy-d-glucose (2-DG), an inhibitor of the glycolytic pathway, markedly inhibited the expressions of Arg, Ym-1, Fizz1, and CD206 molecules, the hall-markers for M2 macrophages, during macrophages were stimulated with interleukin 4. The impacted M2 macrophage polarization by 2-DG is not due to cell death but caused by the impaired cellular glycolysis. Molecular mechanism studies indicate that the effect of 2-DG on M2 polarized macrophages relies on AMPK-Hif-1α-dependent pathways. Importantly, 2-DG treatment significantly decreases anti-inflammatory M2 macrophage polarization and prevents disease progression in a series of mouse models with chitin administration, tumor, and allergic airway inflammation. Thus, the identification of the master role of glycolysis in M2 macrophage polarization offers potential molecular targets for M2 macrophages-mediated diseases. 2-DG therapy may have beneficial effects in patients with tumors or allergic airway inflammation by its negative regulation on M2 macrophage polarization.

Spaceflight and simulated microgravity suppresses macrophage development via altered RAS/ERK/NFκB and metabolic pathways

“…In addition, numerous studies have investigated inflammation-induced metabolic reprogramming in activated macrophages. 22,33 It was reported that glycolysis levels decreased during the immune tolerance period 34 and that proinflammatory macrophages (M1) required more glycolysis than resting macrophages. 35,36 Additionally, the antiinflammatory cytokine IL-10 inhibits glycolysis and promotes oxidative phosphorylation in macrophages.…”

Changes in Nutritional Status Impact Immune Cell Metabolism and Function

“…This suggests the glycolysis pathway as a potential target for the control of inflammation. Multiple reports have shown that the inhibition of glycolysis by 2-deoxyglucose (2-DG) can block CD4+ T cell proliferation, inflammatory macrophage polarization, and B cell survival ( 155 – 157 ). Although 2-DG shows a potent anti-inflammatory activity and has shown tolerability in clinical trials for the treatment of prostate cancer, cardiac adverse reactions to 2-DG were reported ( 158 , 159 ), and alternative targets for the inhibition of glucose metabolism are required.…”

The Role of Metabolic Remodeling in Macrophage Polarization and Its Effect on Skeletal Muscle Regeneration

“…In fact, although FAO decreases during M1 polarization, it has been demonstrated, in both murine and human MF, that etomoxir-mediated FAO inhibition does not block mitochondrial respiration and does not inhibit M2 polarization (237,332,355). Notably, suppression of glucose oxidation (not FAO suppression) would inhibit M2 polarization (332); this hypothesis is corroborated by the observation that 2DG-dependent glycolysis-inhibition-similar to mitochondrial ATPsynthase inhibition by oligomycinblocks respiration and M2 polarization, as observed both in human and in murine MF both in vivo and in vitro (63,246,353,397).…”