Browse > Article

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)
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
Adaptor; Astrocytes; Brain; Endogenous Ligand; Gangliosides; Inflammation; Microglia; Myd88; TLR2;
Citations & Related Records
Times Cited By KSCI : 1  (Citation Analysis)
Times Cited By Web Of Science : 8  (Related Records In Web of Science)
연도 인용수 순위
1 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   DOI   ScienceOn
2 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
3 Lee, M.S. and Kim, Y.J. (2007). Pattern-recognition receptor signaling initiated from extracellular, membrane, and cytoplasmic space. Mol. Cells 23, 1-10
4 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   DOI   ScienceOn
5 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   DOI   ScienceOn
6 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
7 Ulevitch, R. J. (2004). Therapeutics targeting the innate immune system. Nat. Rev. Immunol. 4, 512-520   DOI   ScienceOn
8 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   DOI   ScienceOn
9 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   DOI   ScienceOn
10 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   DOI   ScienceOn
11 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
12 Rajendran, L. and Simons, K. (2005). Lipid rafts and membrane dynamics. J. Cell Sci. 118, 1099-1102   DOI   ScienceOn
13 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   DOI   ScienceOn
14 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   DOI   ScienceOn
15 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   DOI   ScienceOn
16 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
17 Dustin, M.L. (2002). Membrane domains and the immunological synapse: keeping T cells resting and ready. J. Clin. Invest. 109, 155-160
18 Kaisho, T. and Akira, S. (2006). Toll-like receptor function and signaling. J. Allergy Clin. Immunol. 117, 979-987   DOI   ScienceOn
19 Derry, D.M. and Wolfe, L.S. (1967). Gangliosides in isolated neurons and glial cells. Science 158, 1450-1452   DOI
20 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   DOI   ScienceOn
21 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   DOI   ScienceOn
22 Miyake, K. (2007). Innate immune sensing of pathogens and danger signals by cell surface Toll-like receptors. Semin. Immunol. 19, 3-10
23 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
24 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
25 Akira, S. (2003). Mammalian Toll-like receptors. Curr. Opin. Immunol. 15, 5-11   DOI   ScienceOn
26 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   DOI   ScienceOn
27 Kawai, T. and Akira, S. (2007). TLR signaling. Semin. Immunol. 19, 24-32