Molecules and Cells

Korean Society for Molecular and Cellular Biology (한국분자세포생물학회)
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The Effect of Annexin A1 as a Potential New Therapeutic Target on Neuronal Damage by Activated Microglia

  • You, Ji-Eun (Department of Biomedical Laboratory Science, Konyang University) ;
  • Jung, Se-Hwa (Department of Biomedical Laboratory Science, Konyang University) ;
  • Kim, Pyung-Hwan (Department of Biomedical Laboratory Science, Konyang University)
  • Received : 2021.01.29
  • Accepted : 2021.03.15
  • Published : 2021.04.30
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Abstract

Brain disease is known to cause irrevocable and fatal loss of biological function once damaged. One of various causes of its development is damage to neuron cells caused by hyperactivated microglia, which function as immune cells in brain. Among the genes expressed in microglia stimulated by various antigens, annexin A1 (ANXA1) is expressed in the early phase of the inflammatory response and plays an important role in controlling the immune response. In this study, we assessed whether ANXA1 can be a therapeutic target gene for the initial reduction of the immune response induced by microglia to minimize neuronal damage. To address this, mouse-origin microglial cells were stimulated to mimic an immune response by lipopolysaccharide (LPS) treatment. The LPS treatment caused activation of ANXA1 gene and expression of inflammatory cytokines. To assess the biological function in microglia by the downregulation of ANXA1 gene, cells were treated with short hairpin RNA-ANXA1. Downregulated ANXA1 affected the function of mitochondria in the microglia and showed reduced neuronal damage when compared to the control group in the co-culture system. Taken together, our results showed that ANXA1 could be used as a potential therapeutic target for inflammation-related neurodegenerative diseases.

Keywords

Acknowledgement

The research leading to these results received from the Konyang University Research Fund in 2019.

References

  1. Arends, Y., Duyckaerts, C., Rozemuller, J., Eikelenboom, P., and Hauw, J. (2000). Microglia, amyloid and dementia in Alzheimer disease: a correlative study. Neurobiol. Aging 21, 39-47.
  2. Ashrafian, H., Zadeh, E.H., and Khan, R.H. (2020). Review on Alzheimer's disease: inhibition of amyloid beta and tau tangle formation. Int. J. Biol. Macromol. 167, 382-394. https://doi.org/10.1016/j.ijbiomac.2020.11.192
  3. Binder, L.I., Guillozet-Bongaarts, A.L., Garcia-Sierra, F., and Berry, R.W. (2005). Tau, tangles, and Alzheimer's disease. Biochim. Biophys. Acta 1739, 216-223. https://doi.org/10.1016/j.bbadis.2004.08.014
  4. Block, M.L., Zecca, L., and Hong, J.S. (2007). Microglia-mediated neurotoxicity: uncovering the molecular mechanisms. Nat. Rev. Neurosci. 8, 57-69. https://doi.org/10.1038/nrn2038
  5. Buckingham, J.C., John, C.D., Solito, E., Tierney, T., Flower, R.J., Christian, H., and Morris, J. (2006). Annexin 1, glucocorticoids, and the neuroendocrine-immune interface. Ann. N. Y. Acad. Sci. 1088, 396. https://doi.org/10.1196/annals.1366.002
  6. Chan, A., Magnus, T., and Gold, R. (2001). Phagocytosis of apoptotic inflammatory cells by microglia and modulation by different cytokines: mechanism for removal of apoptotic cells in the inflamed nervous system. Glia 33, 87-95. https://doi.org/10.1002/1098-1136(20010101)33:1<87::AID-GLIA1008>3.0.CO;2-S
  7. Choi, E.J., Jeon, C.H., Park, D.H., and Kwon, T.H. (2020). Allithiamine exerts therapeutic effects on sepsis by modulating metabolic flux during dendritic cell activation. Mol. Cells 43, 964-973. https://doi.org/10.14348/molcells.2020.0198
  8. Colonna, M. and Butovsky, O. (2017). Microglia function in the central nervous system during health and neurodegeneration. Annu. Rev. Immunol. 35, 441-468. https://doi.org/10.1146/annurev-immunol-051116-052358
  9. Colton, C.A. and Wilcock, D.M. (2010). Assessing activation states in microglia. CNS Neurol. Disord. Drug Targets 9, 174-191. https://doi.org/10.2174/187152710791012053
  10. Dai, X.J., Li, N., Yu, L., Chen, Z.Y., Hua, R., Qin, X., and Zhang, Y.M. (2015). Activation of BV2 microglia by lipopolysaccharide triggers an inflammatory reaction in PC12 cell apoptosis through a toll-like receptor 4-dependent pathway. Cell Stress Chaperones 20, 321-331. https://doi.org/10.1007/s12192-014-0552-1
  11. Davie, C.A. (2008). A review of Parkinson's disease. Br. Med. Bull. 86, 109-127. https://doi.org/10.1093/bmb/ldn013
  12. Dreier, R., Schmid, K.W., Gerke, V., and Riehemann, K. (1998). Differential expression of annexins I, II and IV in human tissues: an immunohistochemical study. Histochem. Cell Biol. 110, 137-148. https://doi.org/10.1007/s004180050275
  13. Duncan, T. and Valenzuela, M. (2017). Alzheimer's disease, dementia, and stem cell therapy. Stem Cell Res. Ther. 8, 111. https://doi.org/10.1186/s13287-017-0567-5
  14. Eikelenboom, P. and Veerhuis, R. (1996). The role of complement and activated microglia in the pathogenesis of Alzheimer's disease. Neurobiol. Aging 17, 673-680. https://doi.org/10.1016/0197-4580(96)00108-X
  15. Fan, Y., Xie, L., and Chung, C.Y. (2017). Signaling pathways controlling microglia chemotaxis. Mol. Cells 40, 163. https://doi.org/10.14348/molcells.2017.0011
  16. Franco, R. and Fernandez-Suarez, D. (2015). Alternatively activated microglia and macrophages in the central nervous system. Prog. Neurobiol. 131, 65-86. https://doi.org/10.1016/j.pneurobio.2015.05.003
  17. Gordon, S. and Taylor, P.R. (2005). Monocyte and macrophage heterogeneity. Nat. Rev. Immunol. 5, 953-964. https://doi.org/10.1038/nri1733
  18. Graeber, M.B. (2010). Changing face of microglia. Science 330, 783-788. https://doi.org/10.1126/science.1190929
  19. Han, P.F., Che, X.D., Li, H.Z., Gao, Y.Y., Wei, X.C., and Li, P.C. (2020). Annexin A1 involved in the regulation of inflammation and cell signaling pathways. Chin. J. Traumatol. 23, 96-101. https://doi.org/10.1016/j.cjtee.2020.02.002
  20. Hanisch, U.K. and Kettenmann, H. (2007). Microglia: active sensor and versatile effector cells in the normal and pathologic brain. Nat. Neurosci. 10, 1387-1394. https://doi.org/10.1038/nn1997
  21. Henkel, J.S., Beers, D.R., Zhao, W., and Appel, S.H. (2009). Microglia in ALS: the good, the bad, and the resting. J. Neuroimmune Pharmacol. 4, 389-398. https://doi.org/10.1007/s11481-009-9171-5
  22. Jeong, S. (2017). Molecular and cellular basis of neurodegeneration in Alzheimer's disease. Mol. Cells 40, 613. https://doi.org/10.14348/molcells.2017.0096
  23. Katz, I.R., Jeste, D.V., Mintzer, J.E., and Clyde, C. (1999). Comparison of risperidone and placebo for psychosis and behavioral disturbances associated with dementia: a randomized, double-blind trial. J. Clin. Psychiatry 60, 107-115. https://doi.org/10.4088/JCP.v60n0207
  24. Lewcock, J.W., Schlepckow, K., Di Paolo, G., Tahirovic, S., Monroe, K.M., and Haass, C. (2020). Emerging microglia biology defines novel therapeutic approaches for Alzheimer's disease. Neuron 108, 801-821. https://doi.org/10.1016/j.neuron.2020.09.029
  25. Liu, B. and Hong, J.S. (2003). Role of microglia in inflammation-mediated neurodegenerative diseases: mechanisms and strategies for therapeutic intervention. J. Pharmacol. Exp. Ther. 304, 1-7. https://doi.org/10.1124/jpet.102.035048
  26. Ma, H.W., Ye, W., Chen, H.S., Nie, T.J., Cheng, L.F., Zhang, L., Han, P.J., Wu, X.A., Xu, Z.K., and Lei, Y.F. (2017). In-cell western assays to evaluate Hantaan virus replication as a novel approach to screen antiviral molecules and detect neutralizing antibody titers. Front. Cell. Infect. Microbiol. 7, 269. https://doi.org/10.3389/fcimb.2017.00269
  27. Magnus, T., Chan, A., Grauer, O., Toyka, K.V., and Gold, R. (2001). Microglial phagocytosis of apoptotic inflammatory T cells leads to down-regulation of microglial immune activation. J. Immunol. 167, 5004-5010. https://doi.org/10.4049/jimmunol.167.9.5004
  28. Masters, C.L., Bateman, R., Blennow, K., Rowe, C.C., Sperling, R.A., and Cummings, J.L. (2015). Alzheimer's disease. Nat. Rev. Dis. Primers 1, 15056. https://doi.org/10.1038/nrdp.2015.56
  29. McArthur, S., Cristante, E., Paterno, M., Christian, H., Roncaroli, F., Gillies, G.E., and Solito, E. (2010). Annexin A1: a central player in the anti-inflammatory and neuroprotective role of microglia. J. Immunol. 185, 6317-6328. https://doi.org/10.4049/jimmunol.1001095
  30. Nilsson, P., Iwata, N., Muramatsu, S., Tjernberg, L.O., Winblad, B., and Saido, T.C. (2010). Gene therapy in Alzheimer's disease-potential for disease modification. J. Cell. Mol. Med. 14, 741-757. https://doi.org/10.1111/j.1582-4934.2010.01038.x
  31. Nimmerjahn, A., Kirchhoff, F., and Helmchen, F. (2005). Resting microglial cells are highly dynamic surveillants of brain parenchyma in vivo. Science 308, 1314-1318. https://doi.org/10.1126/science.1110647
  32. Pascual, O., Achour, S.B., Rostaing, P., Triller, A., and Bessis, A. (2012). Microglia activation triggers astrocyte-mediated modulation of excitatory neurotransmission. Proc. Natl. Acad. Sci. U. S. A. 109, E197-E205. https://doi.org/10.1073/pnas.1111098109
  33. Perry, V.H., Nicoll, J.A., and Holmes, C. (2010). Microglia in neurodegenerative disease. Nat. Rev. Neurol. 6, 193. https://doi.org/10.1038/nrneurol.2010.17
  34. Picca, A., Calvani, R., Coelho-Junior, H.J., Landi, F., Bernabei, R., and Marzetti, E. (2020). Mitochondrial dysfunction, oxidative stress, and neuroinflammation: intertwined roads to neurodegeneration. Antioxidants (Basel) 9, 647. https://doi.org/10.3390/antiox9080647
  35. Qiu, X., Guo, H., Yang, J., Ji, Y., Wu, C.S., and Chen, X. (2018). Downregulation of guanylate binding protein 1 causes mitochondrial dysfunction and cellular senescence in macrophages. Sci. Rep. 8, 1-12. https://doi.org/10.1038/s41598-017-17765-5
  36. Ramani, P.K. and Sankaran, B.P. (2020). Tay-Sachs disease. In StatPearls [Internet], B. Abai, ed. (Treasure Island: StatPearls Publishing).
  37. Ransohoff, R.M. (2016). A polarizing question: do M1 and M2 microglia exist? Nat. Neurosci. 19, 987. https://doi.org/10.1038/nn.4338
  38. Ransohoff, R.M. and Perry, V.H. (2009). Microglial physiology: unique stimuli, specialized responses. Annu. Rev. Immunol. 27, 119-145. https://doi.org/10.1146/annurev.immunol.021908.132528
  39. Scheiblich, H., Trombly, M., Ramirez, A., and Heneka, M.T. (2020). Neuroimmune connections in aging and neurodegenerative diseases. Trends Immunol. 41, 300-312. https://doi.org/10.1016/j.it.2020.02.002
  40. Shaji, K., Sivakumar, P., Rao, G.P., and Paul, N. (2018). Clinical practice guidelines for management of dementia. Indian J. Psychiatry 60(Suppl 3), S312-S328.
  41. Shin, S.J., Jeon, S.G., Kim, J.I., Jeong, Y.O., Kim, S., Park, Y.H., Lee, S.K., Park, H.H., Hong, S.B., Oh, S., et al. (2019). Red ginseng attenuates Aβ-induced mitochondrial dysfunction and Aβ-mediated pathology in an animal model of Alzheimer's disease. Int. J. Mol. Sci. 20, 3030. https://doi.org/10.3390/ijms20123030
  42. Solito, E., McArthur, S., Christian, H., Gavins, F., Buckingham, J.C., and Gillies, G.E. (2008). Annexin A1 in the brain-undiscovered roles? Trends Pharmacol. Sci. 29, 135-142. https://doi.org/10.1016/j.tips.2007.12.003
  43. Summers, W.K., Majovski, L.V., Marsh, G.M., Tachiki, K., and Kling, A. (1986). Oral tetrahydroaminoacridine in long-term treatment of senile dementia, Alzheimer type. N. Engl. J. Med. 315, 1241-1245. https://doi.org/10.1056/NEJM198611133152001
  44. Tang, Y. and Le, W. (2016). Differential roles of M1 and M2 microglia in neurodegenerative diseases. Mol. Neurobiol. 53, 1181-1194. https://doi.org/10.1007/s12035-014-9070-5
  45. Wang, N., Liang, H., and Zen, K. (2014). Molecular mechanisms that influence the macrophage M1-M2 polarization balance. Front. Immunol. 5, 614. https://doi.org/10.3389/fimmu.2014.00614