Molecules and Cells

Korean Society for Molecular and Cellular Biology (한국분자세포생물학회)
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Contribution of TLR2 to the Initiation of Ganglioside-triggered Inflammatory Signaling

  • Yoon, Hee Jung (Immune and Cell therapy Branch, National Cancer Center) ;
  • Jeon, Sae Bom (Immune and Cell therapy Branch, National Cancer Center) ;
  • Suk, Kyoungho (Department of Pharmacology, Kyungbook National University School of Medicine) ;
  • Choi, Dong-Kug (Department of Biotechnology, Konkuk University) ;
  • Hong, Young-Joon (Department of Laboratory Medicine, Korea Cancer Center Hospital) ;
  • Park, Eun Jung (Immune and Cell therapy Branch, National Cancer Center)
  • Received : 2007.07.16
  • Accepted : 2007.08.03
  • Published : 2008.02.29
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Abstract

Gangliosides, sialic acid-containing glycosphingolipids, are implicated in many neuronal diseases, but the precise molecular mechanisms underlying their pathological activities are poorly understood. Here we report that TLR2 participates in the initiation of ganglioside-triggered inflammatory signaling responses. Using FACS analysis and immunofluorescence microscopy, we found that gangliosides rapidly enhanced the cell surface expression of TLR2 in microglia, while reducing that of TLR4. The ganglioside-dependent increase of TLR2 expression was also observed at the messenger and protein levels. We also showed that gangliosides stimulate the interaction of TLR2 with Myd88, an adaptor for TLRs, and obtained evidence that lipid raft formation is closely associated with the ganglioside-induced activation of TLR2 and subsequent inflammatory signaling. These results collectively suggest that TLR2 contributes to the ability of gangliosides to cause inflammatory conditions in the brain.

Keywords

Acknowledgement

Supported by : Korea Research Foundation, Korea Science and Engineering Foundation

References

  1. Akira, S. (2003). Mammalian Toll-like receptors. Curr. Opin. Immunol. 15, 5-11 https://doi.org/10.1016/S0952-7915(02)00013-4
  2. Blennow, K., Davidsson, P., Wallin, A., Fredman, P., Gottfries, C.G., Karlsson, I., Mansson, J.E., and Svennerholm, L. (1991). Gangliosides in cerebrospinal fluid in 'probable Alzheimer's disease'. Arch. Neurol. 48, 1032-1035 https://doi.org/10.1001/archneur.1991.00530220048018
  3. Derry, D.M. and Wolfe, L.S. (1967). Gangliosides in isolated neurons and glial cells. Science 158, 1450-1452 https://doi.org/10.1126/science.158.3807.1450
  4. Dreyfus, H., Guerold, B., Freysz, L., and Hicks, D. (1997). Successive isolation and separation of the major lipid fractions including gangliosides from single biological samples. Anal. Biochem. 249, 67-78 https://doi.org/10.1006/abio.1997.2143
  5. Dustin, M.L. (2002). Membrane domains and the immunological synapse: keeping T cells resting and ready. J. Clin. Invest. 109, 155-160
  6. Gisslen, M., Hagberg, L., Norkrans, G., Lekman, A., and Fredman, P. (1997). Increased cerebrospinal fluid ganglioside GM1 concentrations indicating neuronal involvement in all stages of HIV-1 infection. J. Neurovirol. 3, 148-152 https://doi.org/10.3109/13550289709015804
  7. Jou, I., Lee, J.H., Park, S.Y., Yoon, H.J., Joe, E.H., and Park, E.J. (2006). Gangliosides trigger inflammatory responses via TLR4 in brain glia. Am. J. Pathol. 168, 1619-1630 https://doi.org/10.2353/ajpath.2006.050924
  8. Kaisho, T. and Akira, S. (2006). Toll-like receptor function and signaling. J. Allergy Clin. Immunol. 117, 979-987 https://doi.org/10.1016/j.jaci.2006.02.023
  9. Kawai, T. and Akira, S. (2007). TLR signaling. Semin. Immunol. 19, 24-32
  10. Kim, O.S., Park, E.J., Joe, E.H., and Jou, I. (2002). JAK-STAT signaling mediates gangliosides-induced inflammatory responses in brain microglial cells. J. Biol. Chem. 277, 40594-40601 https://doi.org/10.1074/jbc.M203885200
  11. Ledesma, M.D., Da Silva, J.S., Crassaerts, K., Delacourte, A., De Strooper, B., and Dotti, C.G. (2000). Brain plasmin enhances APP alpha-cleavage and Abeta degradation and is reduced in Alzheimer's disease brains. EMBO Rep. 1, 530-535
  12. Lee, M.S. and Kim, Y.J. (2007). Pattern-recognition receptor signaling initiated from extracellular, membrane, and cytoplasmic space. Mol. Cells 23, 1-10
  13. Lee, J.H., Park, E.J., Kim, O.S., Kim, H.Y., Joe, E.H., and Jou, I. (2005). Double-stranded RNA-activated protein kinase is required for the LPS-induced activation of STAT1 inflammatory signaling in rat brain glial cells. Glia 50, 66-79 https://doi.org/10.1002/glia.20156
  14. McLaurin, J., Franklin, T., Fraser, P.E., and Chakrabartty, A. (1998). Structural transitions associated with the interaction of Alzheimer beta-amyloid peptides with gangliosides. J. Biol. Chem. 273, 4506-4515 https://doi.org/10.1074/jbc.273.8.4506
  15. Medzhitov, R., Preston-Hurlburt, P., and Janeway, C.A., Jr. (1997). A human homologue of the Drosophila Toll protein signals activation of adaptive immunity. Nature 388, 394-397 https://doi.org/10.1038/41131
  16. Michikawa, M., Gong, J.S., Fan, Q.W., Sawamura, N., and Yanagisawa, K. (2001). A novel action of alzheimer's amyloid betaprotein (Abeta): oligomeric Abeta promotes lipid release. J. Neurosci. 21, 7226-7235
  17. Miyake, K. (2007). Innate immune sensing of pathogens and danger signals by cell surface Toll-like receptors. Semin. Immunol. 19, 3-10
  18. O'Neill, L.A. (2002). Signal transduction pathways activated by the IL-1 receptor/toll-like receptor superfamily. Curr. Top Microbiol. Immunol. 270, 47-61
  19. Rajendran, L. and Simons, K. (2005). Lipid rafts and membrane dynamics. J. Cell Sci. 118, 1099-1102 https://doi.org/10.1242/jcs.01681
  20. Sabroe, I., Read, R.C., Whyte, M.K., Dockrell, D.H., Vogel, S.N., and Dower, S.K. (2003). Toll-like receptors in health and disease: complex questions remain. J. Immunol. 171, 1630-1635
  21. Sonnino, S. and Chigorno, V. (2000). Ganglioside molecular species containing C18- and C20-sphingosine in mammalian nervous tissues and neuronal cell cultures. Biochim. Biophys. Acta 1469, 63-77 https://doi.org/10.1016/S0005-2736(00)00210-8
  22. Soong, G., Reddy, B., Sokol, S., Adamo, R., and Prince, A. (2004). TLR2 is mobilized into an apical lipid raft receptor complex to signal infection in airway epithelial cells. J. Clin. Invest. 113, 1482-1489
  23. Triantafilou, M., Miyake, K., Golenbock, D.T., and Triantafilou, K. (2002). Mediators of innate immune recognition of bacteria concentrate in lipid rafts and facilitate lipopolysaccharideinduced cell activation. J. Cell Sci. 115, 2603-2611
  24. Ulevitch, R. J. (2004). Therapeutics targeting the innate immune system. Nat. Rev. Immunol. 4, 512-520 https://doi.org/10.1038/nri1396
  25. Wang, S.S., Rymer, D.L., and Good, T.A. (2001). Reduction in cholesterol and sialic acid content protects cells from the toxic effects of beta-amyloid peptides. J. Biol. Chem. 276, 42027-42034 https://doi.org/10.1074/jbc.M102834200
  26. Yanagisawa, K., Odaka, A., Suzuki, N., and Ihara, Y. (1995). GM1 ganglioside-bound amyloid beta-protein (A beta): a possible form of preamyloid in Alzheimer's disease. Nat. Med. 1, 1062-1066 https://doi.org/10.1038/nm1095-1062
  27. Yang, M.S., Park, E.J., Sohn, S., Kwon, H.J., Shin, W.H., Pyo, H.K., Jin, B., Choi, K.S., Jou, I., and Joe, E.H. (2002). Interleukin- 13 and -4 induce death of activated microglia. Glia 38, 273-280 https://doi.org/10.1002/glia.10057