The glycolysis inhibitor 2-deoxyglucose ameliorates adjuvant-induced arthritis by regulating macrophage polarization in an AMPK-dependent manner

Cai, Weiwei; Cheng, Jie; Zong, Shiye; Yu, Yun; Wang, Ying; Song, Yining; He, Rui; Yuan, Siqi; Chen, Tao; Hu, Mei Chen; Pan, You-Sheng; Ma, Ran; Líu, Hao; Fang, Wei

doi:10.1016/j.molimm.2021.10.007

Cited by 26 publications

(13 citation statements)

References 42 publications

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“…Based on these observations, a metabolic reprogramming through the inhibition of glycolysis seems to modulate the polarization of macrophages from an M1 to an M2 phenotype: the glycolysis inhibitor 2-deoxyglucose ameliorates adjuvant-induced arthritis by regulating macrophage polarization in an AMPK-dependent manner ( Figure 3 ) ( 72 ).…”

Section: Macrophages: Polarization and Signaling Pathways Involved In Ramentioning

confidence: 99%

The Role of M1/M2 Macrophage Polarization in Rheumatoid Arthritis Synovitis

et al. 2022

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Innate and adaptive immunity represent a harmonic counterbalanced system involved in the induction, progression, and possibly resolution of the inflammatory reaction that characterize autoimmune rheumatic diseases (ARDs), including rheumatoid arthritis (RA). Although the immunopathophysiological mechanisms of the ARDs are not fully clarified, they are often associated with an inappropriate macrophage/T-cell interaction, where classical (M1) or alternative (M2) macrophage activation may influence the occurrence of T-helper (Th)1 or Th2 responses. In RA patients, M1/Th1 activation occurs in an inflammatory environment dominated by Toll-like receptor (TLR) and interferon (IFN) signaling, and it promotes a massive production of pro-inflammatory cytokines [i.e., tumor necrosis factor-α (TNFα), interleukin (IL)-1, IL-12, IL-18, and IFNγ], chemotactic factors, and matrix metalloproteinases resulting in osteoclastogenesis, erosion, and progressive joint destruction. On the other hand, the activation of M2/Th2 response determines the release of growth factors and cytokines [i.e., IL-4, IL-10, IL-13, and transforming growth factor (TGF)-β] involved in the anti-inflammatory process leading to the clinical remission of RA. Several subtypes of macrophages have been described. Five polarization states from M1 to M2 have been confirmed in in vitro studies analyzing morphological characteristics, gene expression of phenotype markers (CD80, CD86, TLR2, TLR4, or CD206, CD204, CD163, MerTK), and functional aspect, including the production of reactive oxygen species (ROS). An M1 and M2 macrophage imbalance may induce pathological consequences and contribute to several diseases, such as asthma or osteoclastogenesis in RA patients. In addition, the macrophage dynamic polarization from M1 to M2 includes the presence of intermediate polarity stages distinguished by the expression of specific surface markers and the production/release of distinct molecules (i.e., nitric oxide, cytokines), which characterize their morphological and functional state. This suggests a “continuum” of macrophage activation states playing an important role during inflammation and its resolution. This review discusses the importance of the delicate M1/M2 imbalance in the different phases of the inflammatory process together with the identification of specific pathways, cytokines, and chemokines involved, and its clinical outcomes in RA. The analysis of these aspects could shed a light on the abnormal inflammatory activation, leading to novel therapeutical approaches which may contribute to restore the M1/M2 balance.

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Section: Macrophages: Polarization and Signaling Pathways Involved In Ramentioning

confidence: 99%

The Role of M1/M2 Macrophage Polarization in Rheumatoid Arthritis Synovitis

et al. 2022

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“…It is well known that pro-inflammatory macrophages exhibit the Warburg effect. The Warburg effect means increased glycolysis and a weakened tricarboxylic acid (TCA) cycle; however, energy generation in reparative macrophages depends on the TCA cycle, fatty acids oxidation (FAO), and oxidative phosphorylation (OXPHOS) [17][18][19]. Immunometabolism studies have shown that alterations in the metabolic profile of macrophages shape their activation state and function [20].…”

Section: Ivyspring International Publishermentioning

confidence: 99%

“…Immunometabolism studies have shown that alterations in the metabolic profile of macrophages shape their activation state and function [20]. Inhibition of glycolysis can stimulate peritoneal macrophages to transition from a pro-inflammatory phenotype to a reparative phenotype [19]. The fact reveals that interfering with metabolic profiles in macrophages may be critical to regulating phenotype.…”

Section: Ivyspring International Publishermentioning

confidence: 99%

“…The research reveals that a macrophage cell can transit from a proinflammatory phenotype to a reparative phenotype. Recent studies suggest that inhibition of glycolysis or lactate can stimulate this transition in macrophages [19,36]. We analyzed whether lactate promotes the transition of LPS-induced macrophages to a reparative phenotype by activating PKM2.…”

Section: Lactate Inhibits Glycolysis and Promotes The Transition Of L...mentioning

confidence: 99%

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Lactylation of PKM2 Suppresses Inflammatory Metabolic Adaptation in Pro-inflammatory Macrophages

Wang¹,

Yang²,

Yu³

et al. 2022

Int. J. Biol. Sci.

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Emerging evidence suggests that metabolic adaptation is a vital hallmark and prerequisite for macrophage phenotype transition. Pyruvate kinase M2 (PKM2) is an essential molecular determinant of metabolic adaptions in pro-inflammatory macrophages. Post-translational modifications play a central role in the regulation of PKM2. However, doubt remains on whether lactylation in PKM2 exists and how lactylation modulates the function of PKM2. For the first time, our study reports that lactate inhibits the Warburg effect by activating PKM2, promoting the transition of pro-inflammatory macrophages towards a reparative phenotype. We identify PKM2 as a lactylation substrate and confirm that lactylation occurs mainly at the K62 site. We find that lactate increases the lactylation level of PKM2, which inhibits its tetramer-to-dimer transition, promoting its pyruvate kinase activity and reducing nuclear distribution. In short, our study reports a novel post-translational modification type in PKM2 and clarifies its potential role in regulating inflammatory metabolic adaptation in pro-inflammatory macrophages.

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“…In pre-clinical experiments, 2-DG significantly attenuated arthritis progression and reduced adaptive and innate immune cell activation in K/BxN mice (176). Cai et al reported that inducible-nitric oxide synthase expressing M1 macrophages are significantly increased in arthritic joints and that 2-DG can effectively induce arginase 1 expressing M2 macrophages via the AMPK/NF-kB axis (177). Lonidamine, an inhibitor of HK1 and HK2, attenuates joint destruction in collagen-induced arthritis mice (178).…”

Section: Hexokinase Inhibitorsmentioning

confidence: 99%

Glycolysis in Innate Immune Cells Contributes to Autoimmunity

Chen

Zhang

et al. 2022

Front. Immunol.

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Autoimmune diseases (AIDs) refer to connective tissue inflammation caused by aberrant autoantibodies resulting from dysfunctional immune surveillance. Most of the current treatments for AIDs use non-selective immunosuppressive agents. Although these therapies successfully control the disease process, patients experience significant side effects, particularly an increased risk of infection. There is a great need to study the pathogenesis of AIDs to facilitate the development of selective inhibitors for inflammatory signaling to overcome the limitations of traditional therapies. Immune cells alter their predominant metabolic profile from mitochondrial respiration to glycolysis in AIDs. This metabolic reprogramming, known to occur in adaptive immune cells, i.e., B and T lymphocytes, is critical to the pathogenesis of connective tissue inflammation. At the cellular level, this metabolic switch involves multiple signaling molecules, including serine–threonine protein kinase, mammalian target of rapamycin, and phosphoinositide 3-kinase. Although glycolysis is less efficient than mitochondrial respiration in terms of ATP production, immune cells can promote disease progression by enhancing glycolysis to satisfy cellular functions. Recent studies have shown that active glycolytic metabolism may also account for the cellular physiology of innate immune cells in AIDs. However, the mechanism by which glycolysis affects innate immunity and participates in the pathogenesis of AIDs remains to be elucidated. Therefore, we reviewed the molecular mechanisms, including key enzymes, signaling pathways, and inflammatory factors, that could explain the relationship between glycolysis and the pro-inflammatory phenotype of innate immune cells such as neutrophils, macrophages, and dendritic cells. Additionally, we summarize the impact of glycolysis on the pathophysiological processes of AIDs, including systemic lupus erythematosus, rheumatoid arthritis, vasculitis, and ankylosing spondylitis, and discuss potential therapeutic targets. The discovery that immune cell metabolism characterized by glycolysis may regulate inflammation broadens the avenues for treating AIDs by modulating immune cell metabolism.

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The glycolysis inhibitor 2-deoxyglucose ameliorates adjuvant-induced arthritis by regulating macrophage polarization in an AMPK-dependent manner

Cited by 26 publications

References 42 publications

The Role of M1/M2 Macrophage Polarization in Rheumatoid Arthritis Synovitis

The Role of M1/M2 Macrophage Polarization in Rheumatoid Arthritis Synovitis

Lactylation of PKM2 Suppresses Inflammatory Metabolic Adaptation in Pro-inflammatory Macrophages

Glycolysis in Innate Immune Cells Contributes to Autoimmunity

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