Skip to main content
SpringerLink
Log in

IDH2 Deficiency in Microglia Decreases the Pro-inflammatory Response via the ERK and NF-κB Pathways

  • ORIGINAL ARTICLE
  • Published:
Inflammation Aims and scope Submit manuscript

Abstract

In various neuronal diseases, the activation of microglia contributes to the production of excessive neurotoxic factors, such as pro-inflammatory mediators. In particular, the overproduction of pro-inflammatory cytokines and nitric oxide (NO) has critical effects on the development of neurodegenerative diseases and gliomas in the brain. Recent studies have suggested that isocitrate dehydrogenase 2 (IDH2) plays a key role in inducing gliomas and neurodegeneration. IDH2 dysfunction has been linked to various cancers and neurodegenerative diseases associated with uncontrolled inflammatory responses, such as the excessive generation of pro-inflammatory cytokines. In this study, we demonstrate that IDH2 contributes to the regulation of pro-inflammatory mediators in microglia. The downregulation of IDH2 decreased the lipopolysaccharide (LPS)-induced pro-inflammatory response in BV-2 and primary microglial cells. Furthermore, IDH2 deficiency downregulated pro-inflammatory mediators via modulation of the ERK and NF-κB pathways. These results indicate that IDH2 is a potential target for the regulation of pro-inflammatory responses in LPS-activated microglial cells. Our findings also provide a basis for the development of new therapies for pro-inflammatory responses in dysfunction-associated neuronal 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. Smolkova, K., and P. Jezek. 2012. The role of mitochondrial NADPH-dependent isocitrate dehydrogenase in cancer cells. International Journal of Cell Biology 2012: 273947.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  2. Yang, E.S., J.H. Lee, and J.W. Park. 2008. Ethanol induces peroxynitrite-mediated toxicity through inactivation of NADP+-dependent isocitrate dehydrogenase and superoxide dismutase. Biochimie 90: 1316–1324.

    Article  PubMed  CAS  Google Scholar 

  3. Megova, M., J. Drabek, V. Koudelakova, R. Trojanec, O. Kalita, and M. Hajduch. 2014. Isocitrate dehydrogenase 1 and 2 mutations in gliomas. Journal of Neuroscience Research 92: 1611–1620.

    Article  PubMed  CAS  Google Scholar 

  4. Chen, C., Y. Liu, C. Lu, J.R. Cross, J.P.t. Morris, A.S. Shroff, P.S. Ward, J.E. Bradner, C. Thompson, and S.W. Lowe. 2013. Cancer-associated IDH2 mutants drive an acute myeloid leukemia that is susceptible to Brd4 inhibition. Genes & Development 27: 1974–1985.

  5. Wang, P.F., H.W. Song, H.Q. Cai, L.W. Kong, K. Yao, T. Jiang, S.W. Li, and C.X. Yan. 2017. Preoperative inflammation markers and IDH mutation status predict glioblastoma patient survival. Oncotarget 8: 50117–50123.

    PubMed  PubMed Central  Google Scholar 

  6. Zhang, J.M., and J. An. 2007. Cytokines, inflammation, and pain. International Anesthesiology Clinics 45: 27–37.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  7. Shih, R.H., C.Y. Wang, and C.M. Yang. 2015. NF-kappaB signaling pathways in neurological inflammation: a mini review. Frontiers in Molecular Neuroscience 8: 77.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  8. Corps, K.N., T.L. Roth, and D.B. McGavern. 2015. Inflammation and neuroprotection in traumatic brain injury. JAMA Neurology 72 (3): 355–362.

    Article  PubMed  PubMed Central  Google Scholar 

  9. Xanthos, D.N., and J. Sandkuhler. 2014. Neurogenic neuroinflammation: inflammatory CNS reactions in response to neuronal activity. Nature Reviews Neuroscience 15: 43–53.

    Article  PubMed  CAS  Google Scholar 

  10. Graeber, M.B., W. Li, and M.L. Rodriguez. 2011. Role of microglia in CNS inflammation. FEBS Letters 585: 3798–3805.

    Article  PubMed  CAS  Google Scholar 

  11. Stoll, G., S. Jander, and M. Schroeter. 2000. Cytokines in CNS disorders: neurotoxicity versus neuroprotection. Journal of Neural Transmission. Supplementum 59: 81–89.

    PubMed  CAS  Google Scholar 

  12. W.Y. Wang, M.S. Tan, J.T. Yu, L. Tan. 2015. Role of pro-inflammatory cytokines released from microglia in Alzheimer’s disease. Annals of Translational Medicine 3: 136.

  13. Hambardzumyan, D., D.H. Gutmann, and H. Kettenmann. 2016. The role of microglia and macrophages in glioma maintenance and progression. Nature Neuroscience 19: 20–27.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  14. Santa-Cecilia, F.V., B. Socias, M.O. Ouidja, J.E. Sepulveda-Diaz, L. Acuna, R.L. Silva, P.P. Michel, E. Del-Bel, T.M. Cunha, and R. Raisman-Vozari. 2016. Doxycycline suppresses microglial activation by inhibiting the p38 MAPK and NF-kB signaling pathways. Neurotoxicity Research 29: 447–459.

    Article  PubMed  CAS  Google Scholar 

  15. Surh, Y.J., H.K. Na, J.Y. Lee, and Y.S. Keum. 2001. Molecular mechanisms underlying anti-tumor promoting activities of heat-processed Panax ginseng C.A. Meyer. Journal of Korean Medical Science 16 (Suppl): S38–S41.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  16. Kim, S., S.Y. Kim, H.J. Ku, Y.H. Jeon, H.W. Lee, J. Lee, T.K. Kwon, K.M. Park, and J.W. Park. 2014. Suppression of tumorigenesis in mitochondrial NADP(+)-dependent isocitrate dehydrogenase knock-out mice. Biochemical and Biophysical Research Communications 1842: 135–143.

    CAS  Google Scholar 

  17. Brewer, G.J., and J.R. Torricelli. 2007. Isolation and culture of adult neurons and neurospheres. Nature Protocols 2: 1490–1498.

    Article  PubMed  CAS  Google Scholar 

  18. Saura, J., J.M. Tusell, and J. Serratosa. 2003. High-yield isolation of murine microglia by mild trypsinization. Glia 44: 183–189.

    Article  PubMed  Google Scholar 

  19. Kim, T.S., H.S. Choi, B.Y. Ryu, G.T. Gang, S.U. Kim, D.B. Koo, J.M. Kim, J.H. Han, C.K. Park, S. Her, and D.S. Lee. 2010. Real-time in vivo bioluminescence imaging of lentiviral vector-mediated gene transfer in mouse testis. Theriogenology 73: 129–138.

    Article  PubMed  CAS  Google Scholar 

  20. Block, M.L., L. Zecca, and J.S. Hong. 2007. Microglia-mediated neurotoxicity: uncovering the molecular mechanisms. Nature Reviews Neuroscience 8: 57–69.

    Article  PubMed  CAS  Google Scholar 

  21. Perry, V.H., J.A. Nicoll, and C. Holmes. 2010. Microglia in neurodegenerative disease. Nature Reviews Neurology 6: 193–201.

    Article  PubMed  Google Scholar 

  22. Vijitruth, R., M. Liu, D.Y. Choi, X.V. Nguyen, R.L. Hunter, and G. Bing. 2006. Cyclooxygenase-2 mediates microglial activation and secondary dopaminergic cell death in the mouse MPTP model of Parkinson’s disease. Journal of Neuroinflammation 3: 6.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  23. Dawson, V.L., and T.M. Dawson. 1996. Nitric oxide neurotoxicity. Journal of Chemical Neuroanatomy 10: 179–190.

    Article  PubMed  CAS  Google Scholar 

  24. Strauss, K.I. 2008. Antiinflammatory and neuroprotective actions of COX2 inhibitors in the injured brain. Brain, Behavior, and Immunity 22: 285–298.

    Article  PubMed  CAS  Google Scholar 

  25. Kim, S.H., C.J. Smith, and L.J. Van Eldik. 2004. Importance of MAPK pathways for microglial pro-inflammatory cytokine IL-1 beta production. Neurobiology of Aging 25: 431–439.

    Article  PubMed  CAS  Google Scholar 

  26. Chen, W.W., X. Zhang, and W.J. Huang. 2016. Role of neuroinflammation in neurodegenerative diseases (review). Molecular Medicine Reports 13: 3391–3396.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  27. Rock, R.B., G. Gekker, S. Hu, W.S. Sheng, M. Cheeran, J.R. Lokensgard, and P.K. Peterson. 2004. Role of microglia in central nervous system infections. Clinical Microbiology Reviews 17: 942–964.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  28. Baeuerle, P.A., and D. Baltimore. 1996. NF-kappa B: ten years after. Cell 87: 13–20.

    Article  PubMed  CAS  Google Scholar 

  29. Mattson, M.P., and S. Camandola. 2001. NF-kappaB in neuronal plasticity and neurodegenerative disorders. Journal of Clinical Investigation 107: 247–254.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  30. Kaminska, B. 2005. MAPK signalling pathways as molecular targets for anti-inflammatory therapy—from molecular mechanisms to therapeutic benefits. Biochimica et Biophysica Acta 1754: 253–262.

    Article  PubMed  CAS  Google Scholar 

  31. Cohen, A.L., S.L. Holmen, and H. Colman. 2013. IDH1 and IDH2 mutations in gliomas. Current Neurology and Neuroscience Reports 13: 345.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  32. Chanmee, T., P. Ontong, K. Konno, and N. Itano. 2014. Tumor-associated macrophages as major players in the tumor microenvironment. Cancers (Basel) 6: 1670–1690.

    Article  CAS  Google Scholar 

  33. Ku, H.J., Y. Ahn, J.H. Lee, K.M. Park, and J.W. Park. 2015. IDH2 deficiency promotes mitochondrial dysfunction and cardiac hypertrophy in mice. Free Radical Biology & Medicine 80: 84–92.

    Article  CAS  Google Scholar 

  34. Park, J., J.S. Min, B. Kim, U.B. Chae, J.W. Yun, M.S. Choi, I.K. Kong, K.T. Chang, and D.S. Lee. 2015. Mitochondrial ROS govern the LPS-induced pro-inflammatory response in microglia cells by regulating MAPK and NF-kappa B pathways. Neuroscience Letters 584: 191–196.

    Article  PubMed  CAS  Google Scholar 

  35. Turner, M.D., B. Nedjai, T. Hurst, and D.J. Pennington. 2014. Cytokines and chemokines: at the crossroads of cell signalling and inflammatory disease. Biochimica et Biophysica Acta 1843: 2563–2582.

    Article  PubMed  CAS  Google Scholar 

Download references

Funding

This research was supported by grants from the National Research Foundation of Korea, funded by the government of Republic of Korea (NRF-2015R1A4A1042271, NRF-2017R1A2B4008176, NRF-2017R1A5A2015391).

Author information

Authors and Affiliations

  1. School of Life Sciences and Biotechnology, BK21 Plus KNU Creative BioResearch Group, Kyungpook National University, Daegu, Republic of Korea

    Unbin Chae, Han Seop Kim, Kyung-Min Kim, Heejin Lee, Hyun-Shik Lee, Jeen-Woo Park & Dong-Seok Lee

  2. College of Natural Sciences, Kyungpook National University, Daegu, 41566, Republic of Korea

    Unbin Chae, Han Seop Kim, Kyung-Min Kim, Heejin Lee, Hyun-Shik Lee, Jeen-Woo Park & Dong-Seok Lee

  3. New Drug Development Center, DGMIF, Daegu, Republic of Korea

    Heejin Lee

Authors
  1. Unbin Chae
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Han Seop Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Kyung-Min Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Heejin Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Hyun-Shik Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Jeen-Woo Park
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Dong-Seok Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Dong-Seok Lee.

Ethics declarations

All animal experiments performed in accordance with the guidelines of the Animal Care Committee of Kyungpook National University.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Chae, U., Kim, H.S., Kim, KM. et al. IDH2 Deficiency in Microglia Decreases the Pro-inflammatory Response via the ERK and NF-κB Pathways. Inflammation 41, 1965–1973 (2018). https://doi.org/10.1007/s10753-018-0840-5

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10753-018-0840-5

KEY WORDS

Search

Navigation