Skip to main content
SpringerLink
Log in

Propofol regulates activated macrophages metabolism through inhibition of ROS-mediated GLUT1 expression

  • Original Research Paper
  • Published:
Inflammation Research Aims and scope Submit manuscript

Abstract

Objective

Activated macrophages undergo a metabolic shift from oxidative phosphorylation (OXPHOS) to aerobic glycolysis, which plays a critical role in inflammation. Increasing evidence suggests the important role of propofol in the regulation of inflammatory response and metabolism, but the effect of propofol on the metabolic shift in macrophage, and the mechanisms involved remain unclear.

Methods

The effect of propofol on the metabolic switch was analyzed by extracellular acidification rate and oxygen consumption rate assays. The effect of propofol on glycolysis was analyzed by lactate and glucose uptake assay. The mRNA, protein, cell surface levels of glucose transporter 1 (GLUT1) and the silencing of GLUT1 were employed to understand the effects of GLUT1-mediated metabolism by propofol. Finally, to understand the antioxidation of propofol on the regulation of metabolism, the reactive oxygen species (ROS) production and NADPH activity were performed.

Results

We show that propofol can change the metabolic pathway switch from aerobic glycolysis to OXPHOS in LPS-activated macrophages. Moreover, propofol suppresses aerobic glycolysis via inhibited GLUT1-mediated glucose uptake. Furthermore, we show that propofol reduces ROS overproduction, which in turn inhibits GLUT1 expression. Finally, we find that propofol reduces ROS production via inhibits NADPH activity.

Conclusion

These findings shed light on the function and mechanism of propofol in the metabolic switch and highlight the importance of targeting metabolism by propofol in the clinical medication of inflammatory diseases.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Janeway CA Jr, Medzhitov R. Innate immune recognition. Annu Rev Immunol. 2002;20:197–216.

    Article  CAS  Google Scholar 

  2. Seymour CW, Liu VX, Iwashyna TJ, Brunkhorst FM, Rea TD, Scherag A, et al. Assessment of clinical criteria for sepsis: for the third international consensus definitions for sepsis and septic shock (Sepsis-3). JAMA. 2016;315:762–74.

    Article  CAS  Google Scholar 

  3. O’Neill LA, Kishton RJ, Rathmell J. A guide to immunometabolism for immunologists. Nat Rev Immunol. 2016;16:553–65.

    Article  CAS  Google Scholar 

  4. Pearce EL, Pearce EJ. Metabolic pathways in immune cell activation and quiescence. Immunity. 2013;38:633–43.

    Article  CAS  Google Scholar 

  5. Van den Bossche J, O’Neill LA, Menon D. Macrophage immunometabolism: where are we (going)? Trends Immunol. 2017;38:395–406.

    Article  Google Scholar 

  6. Kelly B, O’Neill LAJ. Metabolic reprogramming in macrophages and dendritic cells in innate immunity. Cell Res. 2015;25:771–84.

    Article  Google Scholar 

  7. Russell DG, Huang L, VanderVen BC. Immunometabolism at the interface between macrophages and pathogens. Nat Rev Immunol. 2019;19:291–304.

    Article  CAS  Google Scholar 

  8. Forrester SJ, Kikuchi DS, Hernandes MS, Xu Q, Griendling KK. Reactive oxygen species in metabolic and inflammatory signaling. Circ Res. 2018;122:877.

    Article  CAS  Google Scholar 

  9. Jung KH, Lee JH, Quach CHT, Paik JY, Oh H, Park JW, et al. Resveratrol suppresses cancer cell glucose uptake by targeting reactive oxygen species-mediated hypoxia-inducible factor-1 alpha activation. J Nucl Med. 2013;54:2161–7.

    Article  CAS  Google Scholar 

  10. Ciechanowicz SJ, Ma D. Anaesthesia for oncological surgery—can it really influence cancer recurrence? Anaesthesia. 2016;71:127–31.

    Article  CAS  Google Scholar 

  11. Chen RM, Chen TG, Chen TL, Lin LL, Chang CC, Chang HC, et al. Anti-inflammatory and antioxidative effects of propofol on lipopolysaccharide-activated macrophages. In: Role of the mitochondria in human aging and disease: from genes to cell signalling, vol 1042. Hoboken: Wiley; 2005. p. 262–71.

    Google Scholar 

  12. Liu JH, Li YJ, Xia XH, Yang XY, Zhao RZ, Peer J, et al. Propofol reduces microglia activation and neurotoxicity through inhibition of extracellular vesicle release. J Neuroimmunol. 2019;333:476962.

    Article  CAS  Google Scholar 

  13. Tanaka T, Takabuchi S, Nishi K, Oda S, Wakamatsu T, Daijo H, et al. The intravenous anesthetic propofol inhibits lipopolysaccharide-induced hypoxia-inducible factor 1 activation and suppresses the glucose metabolism in macrophages. J Anesth. 2010;24:54–60.

    Article  Google Scholar 

  14. Zhong HH, Song R, Pang QN, Liu YW, Zhuang JL, Chen YM, et al. Propofol inhibits parthanatos via ROS-ER-calcium-mitochondria signal pathway in vivo and vitro. Cell Death Dis. 2018;9:932.

    Article  Google Scholar 

  15. Qi J, Wu QC, Zhu XQ, Zhang S, Chen XY, Chen WK, et al. Propofol attenuates the adhesion of tumor and endothelial cells through inhibiting glycolysis in human umbilical vein endothelial cells. Acta Biochim Biophs Sin. 2019;51:1114–22.

    CAS  Google Scholar 

  16. Sumi C, Okamoto A, Tanaka H, Nishi K, Kusunoki M, Shoji T, et al. Propofol induces a metabolic switch to glycolysis and cell death in a mitochondrial electron transport chain-dependent manner. PLoS ONE. 2018;13:e0192796.

    Article  Google Scholar 

  17. Kawai T, Akira S. The role of pattern-recognition receptors in innate immunity: update on toll-like receptors. Nat Immunol. 2010;11:373–84.

    Article  CAS  Google Scholar 

  18. Osborn O, Olefsky JM. The cellular and signaling networks linking the immune system and metabolism in disease. Nat Med. 2012;18:363–74.

    Article  CAS  Google Scholar 

  19. Chen X, Lu P, Chen L, Yang SJ, Shen HY, Yu DD, et al. Perioperative propofol-paravertebral anesthesia decreases the metastasis and progression of breast cancer. Tumour Biol. 2015;36:8259–66.

    Article  CAS  Google Scholar 

  20. Xu YJ, Li SY, Cheng Q, Chen WK, Wang SL, Ren Y, et al. Effects of anaesthesia on proliferation, invasion and apoptosis of LoVo colon cancer cells in vitro. Anaesthesia. 2016;71:147–54.

    Article  CAS  Google Scholar 

  21. Chen XY, Wu QC, You L, Chen SS, Zhu MM, Miao CH. Propofol attenuates pancreatic cancer malignant potential via inhibition of NMDA receptor. Eur J Pharmacol. 2017;795:150–9.

    Article  CAS  Google Scholar 

  22. Freemerman AJ, Johnson AR, Sacks GN, Milner JJ, Kirk EL, Troester MA, et al. Metabolic reprogramming of macrophages glucose transporter 1 (GLUT1)-mediated glucose metabolism drives a proinflammatory phenotype. J Biol Chem. 2014;289:7884–96.

    Article  CAS  Google Scholar 

  23. Talwar H, Bouhamdan M, Bauerfeld C, Talreja TJ, Aoidi R, Houde N, et al. MEK2 negatively regulates lipopolysaccharide-mediated IL-1 beta production through HIF-1 alpha expression. J Immunol. 2019;202:1815–25.

    Article  CAS  Google Scholar 

  24. Nishi K, Oda T, Takabuchi S, Oda S, Fukuda K, Adachi T, et al. LPS induces hypoxia-inducible factor 1 activation in macrophage-differentiated cells in a reactive oxygen species—dependent manner. Antioxid Redox Signal. 2008;10:983–95.

    Article  CAS  Google Scholar 

  25. Chen X, Wu Q, Sun P, Zhao Y, Zhu M, Miao C. Propofol disrupts aerobic glycolysis in colorectal cancer cells via inactivation of the NMDAR-CAMKII-ERK pathway. Cell Physiol Biochem. 2018;46:492–504.

    Article  CAS  Google Scholar 

  26. Sumi C, Okamoto A, Tanaka H, Kusunoki M, Shoji T, Uba T, et al. Suppression of mitochondrial oxygen metabolism mediated by the transcription factor HIF-1 alleviates propofol-induced cell toxicity. Sci Rep. 2018;8:8987.

    Article  Google Scholar 

  27. Chen RM, Wu CH, Chang HC, Wu GJ, Lin YL, Sheu JR, et al. Propofol suppresses macrophage functions and modulates mitochondrial membrane potential and cellular adenosine triphosphate synthesis. Anesthesiology. 2003;98:1178–85.

    Article  CAS  Google Scholar 

  28. Carruthers A, DeZutter J, Ganguly A, Devaskar SU. Will the original glucose transporter isoform please stand up! Am J Physiol Endocrinol Metab. 2009;297:E836–48.

    Article  CAS  Google Scholar 

  29. Watanabe R, Hilhorst M, Zhang H, Zeisbrich M, Berry GJ, Wallis BB, et al. Glucose metabolism controls disease-specific signatures of macrophage effector functions. JCI Insight. 2018;3:e123047.

    Article  Google Scholar 

  30. Pinheiro CH, Silveira LR, Nachbar RT, Vitzel KF, Curi R. Regulation of glycolysis and expression of glucose metabolism-related genes by reactive oxygen species in contracting skeletal muscle cells. Free Radical Biol Med. 2010;48:953–60.

    Article  CAS  Google Scholar 

  31. Liemburg-Apers DC, Willems PHGM, Koopman WJH, Grefte S. Interactions between mitochondrial reactive oxygen species and cellular glucose metabolism. Arch Toxicol. 2015;89:1209–26.

    Article  CAS  Google Scholar 

  32. Lopez-Pascual A, Lorente-Cebrian S, Moreno-Aliaga MJ, Martinez JA, Gonzalez-Muniesa P. Inflammation stimulates hypoxia-inducible factor-1 alpha regulatory activity in 3T3-L1 adipocytes with conditioned medium from lipopolysaccharide-activated RAW 264.7 macrophages. J Cell Physiol. 2019;234:550–60.

    Article  CAS  Google Scholar 

  33. Hayashi M, Sakata M, Takeda T, Yamamoto T, Okamoto Y, Sawada K, et al. Induction of glucose transporter 1 expression through hypoxia-inducible factor 1 alpha under hypoxic conditions in trophoblast-derived cells. J Endocrinol. 2004;183:145–54.

    Article  CAS  Google Scholar 

  34. Ham M, Lee JW, Choi AH, Jang H, Choi G, Park J, et al. Macrophage glucose-6-phosphate dehydrogenase stimulates proinflammatory responses with oxidative stress. Mol Cell Biol. 2013;33:2425–35.

    Article  CAS  Google Scholar 

  35. Xu KJ, He ZY, Chen M, Wang NF, Zhang DC, Yang L, et al. HIF-1 alpha regulates cellular metabolism, and Imatinib resistance by targeting phosphogluconate dehydrogenase in gastrointestinal stromal tumors. Cell Death Dis. 2020;11:586.

    Article  CAS  Google Scholar 

  36. Freemerman AJ, Zhao LY, Pingili AK, Teng B, Cozzo AJ, Fuller AM, et al. Myeloid Slc2a1-deficient murine model revealed macrophage activation and metabolic phenotype are fueled by GLUT1. J Immunol. 2019;202:1265–86.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This study was supported by Pharmacy Research of Guangdong Provincial Hospital (No. 2020XC25). We thank Kexuan Liu, Chai Li (Southern Medical University) for their technical assistance.

Author information

Authors and Affiliations

  1. Department of Anesthesiology, Affiliated Boai Hospital of Zhongshan, Southern Medical University, Guangdong, 528400, China

    Wei Zeng, Zeting Xing, Meiyun Tan, Yanwen Wu & Chunyuan Zhang

Authors
  1. Wei Zeng
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Zeting Xing
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Meiyun Tan
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yanwen Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Chunyuan Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

CZ devised the concept, designed the research and wrote the paper. WZ performed experiments, analyzed data and designed the figures. ZX, MT, and YW performed the experiments. The final version of the manuscript was approved by all the authors.

Corresponding author

Correspondence to Chunyuan Zhang.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Additional information

Responsible Editor: John Di Battista.

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Zeng, W., Xing, Z., Tan, M. et al. Propofol regulates activated macrophages metabolism through inhibition of ROS-mediated GLUT1 expression. Inflamm. Res. 70, 473–481 (2021). https://doi.org/10.1007/s00011-021-01449-y

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00011-021-01449-y

Keywords

Search

Navigation