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Anti-inflammatory Effects of Metformin on Neuro-inflammation and NLRP3 Inflammasome Activation in BV-2 Microglial Cells

  • Ha, Ji-Sun (Department of Biomedical Laboratory Science, Konyang University) ;
  • Yeom, Yun-Seon (Department of Biomedical Laboratory Science, Konyang University) ;
  • Jang, Ju-Hun (Department of Biomedical Laboratory Science, Konyang University) ;
  • Kim, Yong-Hee (Department of Biomedical Laboratory Science, Konyang University) ;
  • Im, Ji In (Department of Biomedical Laboratory Science, Konyang University) ;
  • Kim, In Sik (Department of Biomedical Laboratory Science, School of Medicine, Eulji University) ;
  • Yang, Seung-Ju (Department of Biomedical Laboratory Science, Konyang University)
  • Received : 2019.02.28
  • Accepted : 2019.03.22
  • Published : 2019.03.31

Abstract

Metformin is a drug used for the treatment of diabetes and is associated with anti-inflammatory reaction, but the underlying mechanism is unclear. In this study, we investigated the effect of metformin on the inflammatory response in BV-2 microglial cells induced by lipopolysaccharide (LPS) and S100 calcium-binding protein A8 (S100A8). The results revealed that metformin significantly attenuated several inflammatory responses in BV-2 microglial cells, including the secretion of pro-inflammatory cytokines, such as tumor necrosis factor-${\alpha}$ and interleukin (IL)-6, involved in the activation of Beclin-1, a crucial regulator of autophagy. In addition, metformin inhibited the LPS-induced phosphorylation of ERK. Metformin also suppressed the activation of NOD-like receptor pyrin domain containing 3 inflammasomes composed of NLRP3, caspase-1, and apoptosis-associated speck like protein containing a caspase recruitment domain, which are involved in the innate immune response. Notably, metformin decreased the secretion of S100A8-induced IL-6 production. These findings suggest that metformin alleviates the neuroinflammatory response via autophagy activation.

Keywords

References

  1. Abderrazak A, Syrovets T, Couchie D, El Hadri K, Friguet B, Simmet T, Rouis M. Nlrp3 inflammasome: From a danger signal sensor to a regulatory node of oxidative stress and inflammatory diseases. Redox Biol. 2015. 4: 296-307. https://doi.org/10.1016/j.redox.2015.01.008
  2. Bauernfeind F, Horvath G, Stutz A, Alnemri ES, MacDonald K, Speert D, Fernandes-Alnemri T, Wu J, Monks BG, Fitzgerald KA, Hornung V, Latz E. Nf-kb activating pattern recognition and cytokine receptors license nlrp3 inflammasome activation by regulating nlrp3 expression. J Immunol. 2009. 183: 787-791. https://doi.org/10.4049/jimmunol.0901363
  3. Chen Y, Zhou K, Wang R, Liu Y, Kwak YD, Ma T, Thompson RC, Zhao Y, Smith L, Gasparini L, Luo Z, Xu H, Liao FF. Antidiabetic drug metformin (glucophager) increases biogenesis of alzheimer's amyloid peptides via up-regulating bace1 transcription. Proceedings of the National Academy of Sciences. 2009. 106: 3907-3912. https://doi.org/10.1073/pnas.0807991106
  4. Cunha C, Gomes C, Vaz AR, Brites D. Exploring new inflammatory biomarkers and pathways during lps-induced m1 polarization. Mediators of Inflammation. 2016. 2016: 1-17.
  5. Fan HH, Zhu LB, Li T, Zhu H, Wang YN, Ren XL, Hu BL, Huang CP, Zhu JH, Zhang X. Hyperoside inhibits lipopolysaccharideinduced inflammatory responses in microglial cells via p38 and nfkappab pathways. Int Immunopharmacol. 2017. 50: 14-21. https://doi.org/10.1016/j.intimp.2017.06.004
  6. Hanisch UK. Microglia as a source and target of cytokines. Glia. 2002. 40: 140-155. https://doi.org/10.1002/glia.10161
  7. Heneka MT, Carson MJ, Khoury JE, Landreth GE, Brosseron F, Feinstein DL, Jacobs AH, Wyss-Coray T, Vitorica J, Ransohoff RM, Herrup K, Frautschy SA, Finsen B, Brown GC, Verkhratsky A, Yamanaka K, Koistinaho J, Latz E, Halle A, Petzold GC, et al. Neuroinflammation in alzheimer's disease. The Lancet Neurology. 2015. 14: 388-405. https://doi.org/10.1016/S1474-4422(15)70016-5
  8. Huang MY, Tu CE, Wang SC, Hung YL, Su CC, Fang SH, Chen CS, Liu PL, Cheng WC, Huang YW, Li CY. Corylin inhibits lps-induced inflammatory response and attenuates the activation of nlrp3 inflammasome in microglia. BMC Complement Altern Med. 2018. 18.
  9. Jo EK, Kim JK, Shin DM, Sasakawa C. Molecular mechanisms regulating nlrp3 inflammasome activation. Cell Mol Immunol. 2016. 13: 148-159. https://doi.org/10.1038/cmi.2015.95
  10. Kim DH, Choi E, Lee JS, Lee NR, Baek SY, Gu A, Kim IS. House dust mite allergen regulates constitutive apoptosis of normal and asthmatic neutrophils via toll-like receptor 4. PLoS One. 2015. 10.
  11. Kim J, Kwak HJ, Cha J-Y, Jeong Y-S, Rhee SD, Kim KR, Cheon HG. Metformin suppresses lipopolysaccharide (lps)-induced inflammatory response in murine macrophages via activating transcription factor-3 (atf-3) induction. Journal of Biological Chemistry. 2014. 289: 23246-23255. https://doi.org/10.1074/jbc.M114.577908
  12. Kuan YC, Huang KW, Lin CL, Hu CJ, Kao CH. Effects of metformin exposure on neurodegenerative diseases in elderly patients with type 2 diabetes mellitus. Prog Neuropsychopharmacol Biol Psychiatry. 2017. 79: 77-83. https://doi.org/10.1016/j.pnpbp.2017.06.002
  13. Levine B, Mizushima N, Virgin HW. Autophagy in immunity and inflammation. Nature. 2011. 469: 323-335. https://doi.org/10.1038/nature09782
  14. Netea-Maier RT, Plantinga TS, van de Veerdonk FL, Smit JW, Netea MG. Modulation of inflammation by autophagy: Consequences for human disease. Autophagy. 2015. 12: 245-260. https://doi.org/10.1080/15548627.2015.1071759
  15. Pan Y, Sun X, Jiang L, Hu L, Kong H, Han Y, Qian C, Song C, Qian Y, Liu W. Metformin reduces morphine tolerance by inhibiting microglial-mediated neuroinflammation. Journal of Neuroinflammation. 2016. 13.
  16. Qian M, Fang X, Wang X. Autophagy and inflammation. Clinical and Translational Medicine. 2017a. 6.
  17. Qian S, Fan J, Billiar TR, Scott MJ. Inflammasome and autophagy regulation: A two-way street. Mol Med. 2017b. 23: 188-195. https://doi.org/10.2119/molmed.2017.00077
  18. Song L, Pei L, Yao S, Wu Y, Shang Y. Nlrp3 inflammasome in neurological diseases, from functions to therapies. Front Cell Neurosci. 2017. 11: 63.
  19. Wang S, Song R, Wang Z, Jing Z, Wang S, Ma J. S100a8/a9 in inflammation. Frontiers in Immunology. 2018. 9.
  20. Whitburn J, Edwards CM, Sooriakumaran P. Metformin and prostate cancer: A new role for an old drug. Curr Urol Rep. 2017. 18.