Advertisement

Inflammation

, Volume 41, Issue 5, pp 1965–1973 | Cite as

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

  • Unbin Chae
  • Han Seop Kim
  • Kyung-Min Kim
  • Heejin Lee
  • Hyun-Shik Lee
  • Jeen-Woo Park
  • Dong-Seok LeeEmail author
ORIGINAL ARTICLE
  • 128 Downloads

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.

KEY WORDS

Isocitrate dehydrogenase 2 Pro-inflammatory mediator Lipopolysaccharide Microglia ERK NF-κB 

Notes

Funding Information

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).

Compliance with Ethical Standards

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

References

  1. 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.CrossRefPubMedPubMedCentralGoogle Scholar
  2. 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.CrossRefPubMedGoogle Scholar
  3. 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.CrossRefPubMedGoogle Scholar
  4. 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.Google Scholar
  5. 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.PubMedPubMedCentralGoogle Scholar
  6. 6.
    Zhang, J.M., and J. An. 2007. Cytokines, inflammation, and pain. International Anesthesiology Clinics 45: 27–37.CrossRefPubMedPubMedCentralGoogle Scholar
  7. 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.CrossRefPubMedPubMedCentralGoogle Scholar
  8. 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.CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Xanthos, D.N., and J. Sandkuhler. 2014. Neurogenic neuroinflammation: inflammatory CNS reactions in response to neuronal activity. Nature Reviews Neuroscience 15: 43–53.CrossRefPubMedGoogle Scholar
  10. 10.
    Graeber, M.B., W. Li, and M.L. Rodriguez. 2011. Role of microglia in CNS inflammation. FEBS Letters 585: 3798–3805.CrossRefPubMedGoogle Scholar
  11. 11.
    Stoll, G., S. Jander, and M. Schroeter. 2000. Cytokines in CNS disorders: neurotoxicity versus neuroprotection. Journal of Neural Transmission. Supplementum 59: 81–89.PubMedGoogle Scholar
  12. 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.Google Scholar
  13. 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.CrossRefPubMedPubMedCentralGoogle Scholar
  14. 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.CrossRefPubMedGoogle Scholar
  15. 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.CrossRefPubMedPubMedCentralGoogle Scholar
  16. 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.Google Scholar
  17. 17.
    Brewer, G.J., and J.R. Torricelli. 2007. Isolation and culture of adult neurons and neurospheres. Nature Protocols 2: 1490–1498.CrossRefPubMedGoogle Scholar
  18. 18.
    Saura, J., J.M. Tusell, and J. Serratosa. 2003. High-yield isolation of murine microglia by mild trypsinization. Glia 44: 183–189.CrossRefPubMedGoogle Scholar
  19. 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.CrossRefPubMedGoogle Scholar
  20. 20.
    Block, M.L., L. Zecca, and J.S. Hong. 2007. Microglia-mediated neurotoxicity: uncovering the molecular mechanisms. Nature Reviews Neuroscience 8: 57–69.CrossRefPubMedGoogle Scholar
  21. 21.
    Perry, V.H., J.A. Nicoll, and C. Holmes. 2010. Microglia in neurodegenerative disease. Nature Reviews Neurology 6: 193–201.CrossRefPubMedGoogle Scholar
  22. 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.CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Dawson, V.L., and T.M. Dawson. 1996. Nitric oxide neurotoxicity. Journal of Chemical Neuroanatomy 10: 179–190.CrossRefPubMedGoogle Scholar
  24. 24.
    Strauss, K.I. 2008. Antiinflammatory and neuroprotective actions of COX2 inhibitors in the injured brain. Brain, Behavior, and Immunity 22: 285–298.CrossRefPubMedGoogle Scholar
  25. 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.CrossRefPubMedGoogle Scholar
  26. 26.
    Chen, W.W., X. Zhang, and W.J. Huang. 2016. Role of neuroinflammation in neurodegenerative diseases (review). Molecular Medicine Reports 13: 3391–3396.CrossRefPubMedPubMedCentralGoogle Scholar
  27. 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.CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Baeuerle, P.A., and D. Baltimore. 1996. NF-kappa B: ten years after. Cell 87: 13–20.CrossRefPubMedGoogle Scholar
  29. 29.
    Mattson, M.P., and S. Camandola. 2001. NF-kappaB in neuronal plasticity and neurodegenerative disorders. Journal of Clinical Investigation 107: 247–254.CrossRefPubMedPubMedCentralGoogle Scholar
  30. 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.CrossRefPubMedGoogle Scholar
  31. 31.
    Cohen, A.L., S.L. Holmen, and H. Colman. 2013. IDH1 and IDH2 mutations in gliomas. Current Neurology and Neuroscience Reports 13: 345.CrossRefPubMedPubMedCentralGoogle Scholar
  32. 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.CrossRefGoogle Scholar
  33. 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.CrossRefGoogle Scholar
  34. 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.CrossRefPubMedGoogle Scholar
  35. 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.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  1. 1.School of Life Sciences and BiotechnologyBK21 Plus KNU Creative BioResearch Group, Kyungpook National UniversityDaeguRepublic of Korea
  2. 2.College of Natural SciencesKyungpook National UniversityDaeguRepublic of Korea
  3. 3.New Drug Development Center, DGMIFDaeguRepublic of Korea

Personalised recommendations