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Reviews in the Neurosciences

Editor-in-Chief: Huston, Joseph P.

Editorial Board: Topic, Bianca / Adeli, Hojjat / Buzsaki, Gyorgy / Crawley, Jacqueline / Crow, Tim / Gold, Paul / Holsboer, Florian / Korth, Carsten / Li, Jay-Shake / Lubec, Gert / McEwen, Bruce / Pan, Weihong / Pletnikov, Mikhail / Robbins, Trevor / Schnitzler, Alfons / Stevens, Charles / Steward, Oswald / Trojanowski, John


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Volume 25, Issue 5

Issues

The role of Toll-like receptors in multiple sclerosis and possible targeting for therapeutic purposes

Maziar Gooshe
  • Research Center for Immunodeficiencies, Children’s Medical Center, Tehran University of Medical Sciences, Tehran 14194, Iran
  • Students’ Scientific Research Center (SSRC), Tehran University of Medical Sciences, Tehran, Iran
  • Other articles by this author:
  • De Gruyter OnlineGoogle Scholar
/ Amir Hossein Abdolghaffari
  • International Campus, ICTUMS, Tehran University of Medical Sciences, Tehran, Iran
  • Institute of Medicinal Plants, Pharmacology and Applied Medicine, Department of Medicinal Plants Research Center, ACECR, Karaj, Iran
  • Other articles by this author:
  • De Gruyter OnlineGoogle Scholar
/ Maria Elsa Gambuzza / Nima Rezaei
  • Corresponding author
  • Research Center for Immunodeficiencies, Children’s Medical Center, Tehran University of Medical Sciences, Tehran 14194, Iran
  • Molecular Immunology Research Center and Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
  • Department of Infection and Immunity, School of Medicine and Biomedical Sciences, University of Sheffield, Sheffield, UK
  • Email
  • Other articles by this author:
  • De Gruyter OnlineGoogle Scholar
Published Online: 2014-06-07 | DOI: https://doi.org/10.1515/revneuro-2014-0026

Abstract

The interaction between the immune and nervous systems suggests invaluable mechanisms for several pathological conditions, especially neurodegenerative disorders. Multiple sclerosis (MS) is a potentially disabling chronic autoimmune disease, characterized by chronic inflammation and neurodegenerative pathology of the central nervous system. Toll-like receptors (TLRs) are an important family of receptors involved in host defense and in recognition of invading pathogens. The role of TLRs in the pathogenesis of autoimmune disorders such as MS is only starting to be uncovered. Recent studies suggest an ameliorative role of TLR3 and a detrimental role of other TLRs in the onset and progression of MS and experimental autoimmune encephalomyelitis, a murine model of MS. Thus, modulating TLRs can represent an innovative immunotherapeutic approach in MS therapy. This article outlines the role of these TLRs in MS, also discussing TLR-targeted agonist or antagonists that could be used in the different stages of the disease.

Keywords: experimental autoimmune encephalomyelitis; multiple sclerosis; Toll-like receptors; treatment

References

  • Akira, S. (2009). Pathogen recognition by innate immunity and its signaling. Proc. Jpn. Acad. Ser. B Phys. Biol. Sci. 85, 143–156.Google Scholar

  • Akira, S. and Takeda, K. (2004). Toll-like receptor signalling. Nat. Rev. Immunol. 4, 499–511.PubMedCrossrefGoogle Scholar

  • Akira, S., Uematsu, S., and Takeuchi, O. (2006). Pathogen recognition and innate immunity. Cell 124, 783–802.Google Scholar

  • Alexopoulou, L., Holt, A.C., Medzhitov, R., Medzhitov, R., and Flavell, R.A. (2001). Recognition of double-stranded RNA and activation of NF-κB by Toll-like receptor 3. Nature 413, 732–738.Google Scholar

  • Aliprantis, A.O., Yang, R.B., Mark, M.R., Suggett, S., Devaux, B., Radolf, J.D., Klimpel, G.R., Godowski, P., and Zychlinsky, A. (1999). Cell activation and apoptosis by bacterial lipoproteins through Toll-like receptor-2. Science 285, 736–739.Google Scholar

  • Amlie-Lefond, C., Paz, D.A., Connelly, M.P., Huffnagle, G.B., Whelan, N.T., and Whelan, H.T. (2005). Innate immunity for biodefense: a strategy whose time has come. J. Allergy Clin. Immunol. 116, 1334–1342.Google Scholar

  • Andersson, A., Covacu, R., Sunnemark, D., Danilov, A.I., Dal Bianco, A., Khademi, M., Wallström, E., Lobell, A., Brundin, L., Lassmann, H., et al. (2008). Pivotal advance: HMGB1 expression in active lesions of human and experimental multiple sclerosis. J. Leukoc. Biol. 84, 1248–1255.Google Scholar

  • Aravalli, R.N., Hu, S., Rowen, T.N., Palmquist, J.M., and Lokensgard, J.R. (2005). Cutting edge: TLR2-mediated proinflammatory cytokine and chemokine production by microglial cells in response to herpes simplex virus. J. Immunol. 175, 4189–4193.Google Scholar

  • Aravalli, R.N., Peterson, P.K., and Lokensgard, J.R. (2007). Toll-like receptors in defense and damage of the central nervous system. J. Neuroimmune Pharmacol. 2, 297–312.Google Scholar

  • Arslan, F., de Kleijn, D.P., Timmers, L., Doevendans, P.A., and Pasterkamp, G. (2008). Bridging innate immunity and myocardial ischemia/reperfusion injury: the search for therapeutic targets. Curr. Pharm. Des. 14, 1205–1216.CrossrefGoogle Scholar

  • Asagiri, M., Hirai, T., Kunigami, T., Kamano, S., Gober, H.J., Okamoto, K., Nishikawa, K., Latz, E., Golenbock, D.T., Aoki, K., et al. (2008). Cathepsin K-dependent Toll-like receptor 9 signaling revealed in experimental arthritis. Science 319, 624–627.Google Scholar

  • Ascherio, A. and Bar-Or, A. (2010). EBV and brain matter(s)? Neurology 74, 1092–1095.CrossrefGoogle Scholar

  • Baldridge, J.R., McGowan, P., Evans, J.T., Cluff, C., Mossman, S., Johnson, D., and Persing, D. (2004). Taking a Toll on human disease: Toll-like receptor 4 agonists as vaccine adjuvants and monotherapeutic agents. Exp. Opin. Biol. Ther. 4, 1129–1138.CrossrefGoogle Scholar

  • Barrat, F.J., Meeker, T., Gregorio, J., Chan, J.H., Uematsu, S., Akira, S., Chang, B., Duramad, O., and Coffman, R.L. (2005). Nucleic acids of mammalian origin can act as endogenous ligands for Toll-like receptors and may promote systemic lupus erythematosus. J. Exp. Med. 202, 1131–1139.Google Scholar

  • Barrat, F.J., Meeker, T., Chan, J.H., Guiducci, C., and Coffman, R.L. (2007). Treatment of lupus-prone mice with a dual inhibitor of TLR7 and TLR9 leads to reduction of autoantibody production and amelioration of disease symptoms. Eur. J. Immunol. 37, 3582–3586.CrossrefGoogle Scholar

  • Bartfai, T., Behrens, M.M., Gaidarova, S., Pemberton, J., Shivanyuk, A., and Rebek, J. Jr. (2003). A low molecular weight mimic of the Toll/IL-1 receptor/resistance domain inhibits IL-1 receptor-mediated responses. Proc. Natl. Acad. Sci. USA 100, 7971–7976.CrossrefGoogle Scholar

  • Bauer, J., Sminia, T., Wouterlood, F.G., and Dijkstra, C.D. (1994). Phagocytic activity of macrophages and microglial cells during the course of acute and chronic relapsing experimental autoimmune encephalomyelitis. J. Neurosci. Res. 38, 365–375.CrossrefGoogle Scholar

  • Bell, J.K., Botos, I., Hall, P.R., Askins, J., Shiloach, J., Segal, D.M., and Davies, D.R. (2005). The molecular structure of the Toll-like receptor 3 ligand-binding domain. Proc. Natl. Acad. Sci. USA 102, 10976–10980.CrossrefGoogle Scholar

  • Benveniste, E.N. (1997). Role of macrophages/microglia in multiple sclerosis and experimental allergic encephalomyelitis. J. Mol. Med. (Berl.) 75, 165–173.CrossrefGoogle Scholar

  • Bhoj, V.G. and Chen, Z.J. (2009). Ubiquitylation in innate and adaptive immunity. Nature 458, 430–437.Google Scholar

  • Bieback, K., Lien, E., Klagge, I.M., Avota, E., Schneider-Schaulies, J., Duprex, W.P., Wagner, H., Kirschning, C.J., Ter Meulen, V., and Schneider-Schaulies. S. (2002). Hemagglutinin protein of wild-type measles virus activates Toll-like receptor 2 signaling. J. Virol. 76, 8729–8736.CrossrefGoogle Scholar

  • Biragyn, A., Ruffini, P.A., Leifer, C.A., Klyushnenkova, E., Shakhov, A., Chertov, O., Shirakawa, A.K., Farber, J.M., Segal, D.M., Oppenheim, J.J., et al. (2002). Toll-like receptor 4-dependent activation of dendritic cells by beta-defensin 2. Science 298, 1025–1029.Google Scholar

  • Blasius, A.L. and Beutler, B. (2010). Intracellular Toll-like receptors. Immunity 32, 305–315.PubMedCrossrefGoogle Scholar

  • Boone, D.L., Turer, E.E., Lee, E.G., Ahmad, R.C., Wheeler, M.T., Tsui, C., Hurley, P., Chien, M., Chai, S., Hitotsumatsu, O., et al. (2004). The ubiquitin-modifying enzyme A20 is required for termination of Toll-like receptor responses. Nat. Immunol. 5, 1052–1060.CrossrefGoogle Scholar

  • Boster, A., Ankeny, D.P., and Racke, M.K. (2010). The potential role of B cell-targeted therapies in multiple sclerosis. Drugs 70, 2343–2356.PubMedCrossrefGoogle Scholar

  • Botos, I., Segal, D.M., and Davies, D.R. (2011). The structural biology of Toll-like receptors. Structure 19, 447–459.PubMedCrossrefGoogle Scholar

  • Bowman, C.C., Rasley, A., Tranguch, S.L., and Marriott, I. (2003). Cultured astrocytes express Toll-like receptors for bacterial products. Glia 43, 281–291.PubMedCrossrefGoogle Scholar

  • Brikos, C. and O’Neill, L.A. (2008). Signalling of Toll-like receptors. Handb. Exp. Pharmacol. 183, 21–50.Google Scholar

  • Broadley, S.A., Vanags, D., Williams, B., Johnson, B., Feeney, D., Griffiths, L., Shakib, S., Brown, G., Coulthard, A., Mullins, P., et al. (2009). Results of a phase IIa clinical trial of an anti-inflammatory molecule, chaperonin 10, in multiple sclerosis. Mult. Scler. 15, 329–336.CrossrefPubMedGoogle Scholar

  • Broudy, V.C., Kaushansky, K., Segal, G.M., Harlan, J.M., and Adamson, J.W. (1986). Tumor necrosis factor type alpha stimulates human endothelial cells to produce granulocyte/macrophage colony-stimulating factor. Proc. Natl. Acad. Sci. USA 83, 7467–7471.Google Scholar

  • Bsibsi, M., Ravid, R., Gveric, D., and van Noort, J.M. (2002). Broad expression of Toll-like receptors in the human central nervous system. J. Neuropathol. Exp. Neurol. 61, 1013–1021.Google Scholar

  • Bsibsi, M., Bajramovic, J.J., Vogt, M.H., van Duijvenvoorden, E., Baghat, A., Persoon-Deen, C., Tielen, F., Verbeek, R., Huitinga, I., Ryffel, B., et al. (2010). The microtubule regulator stathmin is an endogenous protein agonist for TLR3. J. Immunol. 184, 6929–6937.Google Scholar

  • Bulut, Y., Faure, E., Thomas, L., Equils, O., and Arditi, M. (2001). Cooperation of Toll-like receptor 2 and 6 for cellular activation by soluble tuberculosis factor and Borrelia burgdorferi outer surface protein A lipoprotein: role of Toll-interacting protein and IL-1 receptor signaling molecules in Toll-like receptor 2 signaling. J. Immunol. 167, 987–994.Google Scholar

  • Bulut, Y., Faure, E., Thomas, L., Karahashi, H., Michelsen, K.S., Equils, O., Morrison, S.G., Morrison, R.P., and Arditi, M. (2002). Chlamydial heat shock protein 60 activates macrophages and endothelial cells through Toll-like receptor 4 and MD2 in a MyD88-dependent pathway. J. Immunol. 168, 1435–1440.Google Scholar

  • Burdelya, L.G., Krivokrysenko, V.I., Tallant, T.C., Strom, E., Gleiberman, A.S., Gupta, D., Kurnasov, O.V., Fort, F.L., Osterman, A.L., Didonato, J.A., et al. (2008). An agonist of Toll-like receptor 5 has radioprotective activity in mouse and primate models. Science 320, 226–230.Google Scholar

  • Burns, K., Janssens, S., Brissoni, B., Olivos, N., Beyaert, R., and Tschopp, J. (2003). Inhibition of interleukin 1 receptor/Toll-like receptor signaling through the alternatively spliced, short form of MyD88 is due to its failure to recruit IRAK-4. J. Exp. Med. 197, 263–268.Google Scholar

  • Carpenter, S. and O’Neill, L.A. (2009). Recent insights into the structure of Toll-like receptors and post-translational modifications of their associated signalling proteins. Biochem. J. 422, 1–10.Google Scholar

  • Carty, M. and Bowie, A.G. (2011). Evaluating the role of Toll-like receptors in diseases of the central nervous system. Biochem. Pharmacol. 81, 825–837.CrossrefPubMedGoogle Scholar

  • Castro-Borrero, W., Graves, D., Frohman, T.C., Flores, A.B., Hardeman, P., Logan, D., Orchard, M., Greenberg, B., and Frohman, E.M. (2012). Current and emerging therapies in multiple sclerosis: a systematic review. Ther. Adv. Neurol. Disord. 5, 205–220.CrossrefGoogle Scholar

  • Chakrabarti, A., Jha, B.K., and Silverman, R.H. (2011). New insights into the role of RNase L in innate immunity. J. Interferon Cytokine Res. 31, 49–57.Google Scholar

  • Chang, Y.C., Kao, W.C., Wang, W.Y., Yang, R.B., and Peck, K. (2009). Identification and characterization of oligonucleotides that inhibit Toll-like receptor 2-associated immune responses. FASEB. J. 23, 3078–3088.PubMedCrossrefGoogle Scholar

  • Chang, C.I., Lee, T.Y., Kim, S., Sun, X., Hong, S.W., Yoo, J.W., Dua, P., Kang, H.S., Kim, S., Li, C.J., et al. (2012). Enhanced intracellular delivery and multi-target gene silencing triggered by tripodal RNA structures. J. Gene Med. 14, 138–146.CrossrefGoogle Scholar

  • Chearwae, W. and Bright, J.J. (2008). 15-deoxy-Delta(12,14)-prostaglandin J(2) and curcumin modulate the expression of Toll-like receptors 4 and 9 in autoimmune T lymphocyte. J. Clin. Immunol. 28, 558–570.Google Scholar

  • Chen, K., Huang, J., Gong, W., Iribarren, P., Dunlop, N.M., and Wang, J.M. (2007). Toll-like receptors in inflammation, infection and cancer. Int. Immunopharmacol. 7, 1271–1285.PubMedCrossrefGoogle Scholar

  • Chen, Q., Davidson, T.S., Huter, E.N., and Shevach, E.M. (2009). Engagement of TLR2 does not reverse the suppressor function of mouse regulatory T cells, but promotes their survival. J. Immunol. 183, 4458–4466.Google Scholar

  • Christ, W.J., Asano, O., Robidoux, A.L., Perez, M., Wang, Y., Dubuc, G.R., Gavin, W.E., Hawkins, L.D., McGuinness, P.D., Mullarkey, M.A., et al. (1995). E5531, a pure endotoxin antagonist of high potency. Science 268, 80–83.Google Scholar

  • Christensen, S.R., Shupe, J., Nickerson, K., Kashgarian, M., Flavell, R.A., and Shlomchik, M.J. (2006). Toll-like receptor 7 and TLR9 dictate autoantibody specificity and have opposing inflammatory and regulatory roles in a murine model of lupus. Immunity 25, 417–428.CrossrefGoogle Scholar

  • Cluff, C.W., Baldridge, J.R., Stöver, A.G., Evans, J.T., Johnson, D.A., Lacy, M.J., Clawson, V.G., Yorgensen, V.M., Johnson, C.L., Livesay, M.T., et al. (2005). Synthetic Toll-like receptor 4 agonists stimulate innate resistance to infectious challenge. Infect. Immun. 73, 3044–3052.CrossrefGoogle Scholar

  • Coban, C., Ishii, K.J., Kawai, T., Hemmi, H., Sato, S., Uematsu, S., Yamamoto, M., Takeuchi, O., Itagaki, S., Kumar, N., et al. (2005). Toll-like receptor 9 mediates innate immune activation by the malaria pigment hemozoin. J. Exp. Med. 201, 19–25.Google Scholar

  • Codarri, L., Gyülvészi, G., Tosevski, V., Hesske, L., Fontana, A., Magnenat, L., Suter, T., and Becher, B. (2011). RORgammat drives production of the cytokine GM-CSF in helper T cells, which is essential for the effector phase of autoimmune neuroinflammation. Nat. Immunol. 12, 560–567.PubMedCrossrefGoogle Scholar

  • Coelho, P.S., Klein, A., Talvani, A., Coutinho, S.F., Takeuchi, O., Akira, S., Silva, J.S., Canizzaro, H., Gazzinelli, R.T., and Teixeira, M.M. (2002). Glycosylphosphatidylinositol-anchored mucin-like glycoproteins isolated from Trypanosoma cruzi trypomastigotes induce in vivo leukocyte recruitment dependent on MCP-1 production by IFN-gamma-primed-macrophages. J. Leukoc. Biol. 71, 837–844.Google Scholar

  • Compton, T., Kurt-Jones, E.A., Boehme, K.W., Belko, J., Latz, E., Golenbock, D.T., and Finberg, R.W. (2003). Human cytomegalovirus activates inflammatory cytokine responses via CD14 and Toll-like receptor 2. J. Virol. 77, 4588–4596.CrossrefGoogle Scholar

  • Constantinescu, C.S., Farooqi, N., O’Brien, K., and Gran, B. (2011). Experimental autoimmune encephalomyelitis (EAE) as a model for multiple sclerosis (MS). Br. J. Pharmacol. 164, 1079–1106.Google Scholar

  • Coornaert, B., Carpentier, I., and Beyaert, R. (2009). A20: central gatekeeper in inflammation and immunity. J. Biol. Chem. 284, 8217–8221.Google Scholar

  • Couture, L.A., Piao, W., Ru, L.W., Vogel, S.N., and Toshchakov, V.Y. (2012). Targeting Toll-like receptor (TLR) signaling by Toll/interleukin-1 receptor (TIR) domain-containing adapter protein/MyD88 adapter-like (TIRAP/Mal)-derived decoy peptides. J. Biol. Chem. 287, 24641–24648.Google Scholar

  • Curtin, F., Lang, A.B., Perron, H., Laumonier, M., Vidal, V., Porchet, H.C., and Hartung, H.P. (2012). GNbAC1, a humanized monoclonal antibody against the envelope protein of multiple sclerosis-associated endogenous retrovirus: a first-in-humans randomized clinical study. Clin. Ther. 34, 2268–2278.CrossrefGoogle Scholar

  • David, S.A. (2001). Towards a rational development of anti-endotoxin agents: novel approaches to sequestration of bacterial endotoxins with small molecules. J. Mol. Recognit. 14, 370–387.CrossrefGoogle Scholar

  • DeLuca, J. and Nocentini, U. (2011). Neuropsychological, medical and rehabilitative management of persons with multiple sclerosis. NeuroRehabilitation 29, 197–219.PubMedGoogle Scholar

  • Deng, C., Radu, C., Diab, A., Tsen, M.F., Hussain, R., Cowdery, J.S., Racke, M.K., and Thomas, J.A. (2003). IL-1 receptor-associated kinase 1 regulates susceptibility to organ-specific autoimmunity. J. Immunol. 170, 2833–2842.Google Scholar

  • Deretic, V. (2011). Autophagy in immunity and cell-autonomous defense against intracellular microbes. Immunol. Rev. 240, 92–104.Google Scholar

  • Devaux, B., Enderlin, F., Wallner, B., and Smilek, D.E. (1997). Induction of EAE in mice with recombinant human MOG, and treatment of EAE with a MOG peptide. J. Neuroimmunol. 75, 169–173.CrossrefGoogle Scholar

  • Diebold, S.S., Kaisho, T., Hemmi, H., Akira, S., and Reis e Sousa, C. (2004). Innate antiviral responses by means of TLR7-mediated recognition of single-stranded RNA. Science 303, 1529–1531.Google Scholar

  • Diestel, A., Aktas, O., Hackel, D., Hake, I., Meier, S., Raine, C.S., Nitsch, R., Zipp, F., and Ullrich, O. (2003). Activation of microglial poly(ADP-ribose)-polymerase-1 by cholesterol breakdown products during neuroinflammation: a link between demyelination and neuronal damage. J. Exp. Med. 198, 1729–1740.CrossrefGoogle Scholar

  • Dulay, A.T., Buhimschi, C.S., Zhao, G., Oliver, E.A., Mbele, A., Jing, S., and Buhimschi, I.A. (2009). Soluble TLR2 is present in human amniotic fluid and modulates the intraamniotic inflammatory response to infection. J. Immunol. 182, 7244–7253.Google Scholar

  • Dunn-Siegrist, I., Leger, O., Daubeuf, B., Poitevin, Y., Dépis, F., Herren, S., Kosco-Vilbois, M., Dean, Y., Pugin, J., and Elson, G. (2007). Pivotal involvement of Fcgamma receptor IIA in the neutralization of lipopolysaccharide signaling via a potent novel anti-TLR4 monoclonal antibody 15C1. J. Biol. Chem. 282, 34817–34827.Google Scholar

  • Duramad, O., Fearon, K.L., Chang, B., Chan, J.H., Gregorio, J., Coffman, R.L., and Barrat, F.J. (2005). Inhibitors of TLR-9 act on multiple cell subsets in mouse and man in vitro and prevent death in vivo from systemic inflammation. J. Immunol. 174, 5193–5200.CrossrefGoogle Scholar

  • Dutta, R. and Trapp, B.D. (2011). Mechanisms of neuronal dysfunction and degeneration in multiple sclerosis. Prog. Neurobiol. 93, 1–12.PubMedCrossrefGoogle Scholar

  • Elinav, E., Strowig, T., Henao-Mejia, J., and Flavell, R.A. (2011). Regulation of the antimicrobial response by NLR proteins. Immunity 34, 665–679.PubMedCrossrefGoogle Scholar

  • Ellestad, K.K., Tsutsui, S., Noorbakhsh, F., Warren, K.G., Yong, V.W., Pittman, Q.J., and Power, C. (2009). Early life exposure to lipopolysaccharide suppresses experimental autoimmune encephalomyelitis by promoting tolerogenic dendritic cells and regulatory T cells. J. Immunol. 183, 298–309.Google Scholar

  • Eriksson, M., Meadows, S.K., Basu, S., Mselle, T.F., Wira, C.R., and Sentman, C.L. (2006). TLRs mediate IFN-gamma production by human uterine NK cells in endometrium. J. Immunol. 176, 6219–6224.Google Scholar

  • Farez, M.F., Quintana, F.J., Gandhi, R., Izquierdo, G., Lucas, M., and Weiner, H.L. (2009). Toll-like receptor 2 and poly(ADP-ribose) polymerase 1 promote central nervous system neuroinflammation in progressive EAE. Nat. Immunol. 10, 958–964.PubMedGoogle Scholar

  • Farina, C., Aloisi, F., and Meinl, E. (2007). Astrocytes are active players in cerebral innate immunity. Trends Immunol. 28, 138–145.PubMedCrossrefGoogle Scholar

  • Firouzi, R., Rolland, A., Michel, M., Jouvin-Marche, E., Hauw, J.J., Malcus-Vocanson, C., Lazarini, F., Gebuhrer, L., Seigneurin, J.M., Touraine, J.L., et al. (2003). Multiple sclerosis-associated retrovirus particles cause T lymphocyte-dependent death with brain hemorrhage in humanized SCID mice model. J. Neurovirol. 9, 79–93.CrossrefGoogle Scholar

  • Fitzgerald, D.C., Ciric, B., Touil, T., Harle, H., Grammatikopolou, J., Das Sarma, J., Gran, B., Zhang, G.X., and Rostami, A. (2007). Suppressive effect of IL-27 on encephalitogenic Th17 cells and the effector phase of experimental autoimmune encephalomyelitis. J. Immunol. 179, 3268–3275.Google Scholar

  • Fort, M.M., Mozaffarian, A., Stöver, A.G., Correia Jda, S., Johnson, D.A., Crane, R.T., Ulevitch, R.J., Persing, D.H., Bielefeldt-Ohmann, H., Probst, P., et al. (2005). A synthetic TLR4 antagonist has anti-inflammatory effects in two murine models of inflammatory bowel disease. J. Immunol. 174, 6416–6423.CrossrefGoogle Scholar

  • Franciotta, D., Salvetti, M., Lolli, F., Serafini, B., and Aloisi, F. (2008). B cells and multiple sclerosis. Lancet Neurol. 7, 852–858.CrossrefGoogle Scholar

  • Frohman, E.M., Racke, M.K., and Raine, C.S. (2006). Multiple sclerosis – the plaque and its pathogenesis. N. Engl. J. Med. 354, 942–955.Google Scholar

  • Fukao, T., Tanabe, M., Terauchi, Y., Ota, T., Matsuda, S., Asano, T., Kadowaki, T., Takeuchi, T., and Koyasu, S. (2002). PI3K-mediated negative feedback regulation of IL-12 production in DCs. Nat. Immunol. 3, 875–881.CrossrefGoogle Scholar

  • Gambuzza, M., Licata, N., Palella, E., Celi, D., Foti Cuzzola, V., Italiano, D., Marino, S., and Bramanti, P. (2011). Targeting Toll-like receptors: emerging therapeutics for multiple sclerosis management. J. Neuroimmunol. 239, 1–12.Google Scholar

  • Gay, N.J. and Keith, F.J. (1991). Drosophila Toll and IL-1 receptor. Nature 351, 355–356.Google Scholar

  • Gay, N.J., Gangloff, M., and O’Neill, L.A. (2011). What the Myddosome structure tells us about the initiation of innate immunity. Trends Immunol. 32, 104–109.CrossrefGoogle Scholar

  • Gearing, A.J. (2007). Targeting Toll-like receptors for drug development: a summary of commercial approaches. Immunol. Cell Biol. 85, 490–494.PubMedCrossrefGoogle Scholar

  • Gerondakis, S., Grumont, R.J., and Banerjee, A. (2007). Regulating B-cell activation and survival in response to TLR signals. Immunol. Cell Biol. 85, 471–475.CrossrefPubMedGoogle Scholar

  • Gibson, F.C., 3rd, Ukai, T., and Genco, C.A. (2008). Engagement of specific innate immune signaling pathways during Porphyromonas gingivalis induced chronic inflammation and atherosclerosis. Front. Biosci. 13, 2041–2059.PubMedCrossrefGoogle Scholar

  • Goh, E.T., Arthur, J.S., Cheung, P.C., Cheung, P.C., Akira, S., Toth, R., and Cohen, P. (2012). Identification of the protein kinases that activate the E3 ubiquitin ligase Pellino 1 in the innate immune system. Biochem. J. 441, 339–346.Google Scholar

  • Gomariz, R.P., Gutiérrez-Cañas, I., Arranz, A., Carrión, M., Juarranz, Y., Leceta, J., and Martínez, C. (2010). Peptides targeting Toll-like receptor signalling pathways for novel immune therapeutics. Curr. Pharm. Des. 16, 1063–1080.PubMedCrossrefGoogle Scholar

  • Goverman, J.M. (2011). Immune tolerance in multiple sclerosis. Immunol. Rev. 241, 228–240.CrossrefPubMedGoogle Scholar

  • Guillot, L., Balloy, V., McCormack, F.X., Golenbock, D.T., Chignard, M., and Si-Tahar, M. (2002). Cutting edge: the immunostimulatory activity of the lung surfactant protein-A involves Toll-like receptor 4. J. Immunol. 168, 5989–5992.CrossrefGoogle Scholar

  • Guo, B., Chang, E.Y., and Cheng, G. (2008). The type I IFN induction pathway constrains Th17-mediated autoimmune inflammation in mice. J. Clin. Invest. 118, 1680–1690.CrossrefGoogle Scholar

  • Hajjar, A.M., O’Mahony, D.S., Ozinsky, A., Underhill, D.M., Aderem, A., Klebanoff, S.J., and Wilson, C.B. (2001). Cutting edge: functional interactions between Toll-like receptor (TLR) 2 and TLR1 or TLR6 in response to phenol-soluble modulin. J. Immunol. 166, 15–19.CrossrefGoogle Scholar

  • Hanafy, K.A. and Sloane, J.A. (2011). Regulation of remyelination in multiple sclerosis. FEBS Lett. 585, 3821–3828.Google Scholar

  • Hansen, B.S., Hussain, R.Z., Lovett-Racke, A.E., Thomas, J.A., and Racke, M.K. (2006). Multiple Toll-like receptor agonists act as potent adjuvants in the induction of autoimmunity. J. Neuroimmunol. 172, 94–103.Google Scholar

  • Hauser, S.L., Waubant, E., Arnold, D.L., Vollmer, T., Antel, J., Fox, R.J., Bar-Or, A., Panzara, M., Sarkar, N., Agarwal, S., et al. (2008). B-cell depletion with rituximab in relapsing-remitting multiple sclerosis. N. Engl. J. Med. 358, 676–688.Google Scholar

  • Hayashi, F., Smith, K.D., Ozinsky, A., Hawn, T.R., Yi, E.C., Goodlett, D.R., Eng, J.K., Akira, S., Underhill, D.M., and Aderem, A. (2001). The innate immune response to bacterial flagellin is mediated by Toll-like receptor 5. Nature 410, 1099–1103.Google Scholar

  • Hayashi, T., Yao, S., Crain, B., Chan, M., Tawatao, R.I., Gray, C., Vuong, L., Lao, F., Cottam, H.B., Carson, D.A., et al. (2012). Treatment of autoimmune inflammation by a TLR7 ligand regulating the innate immune system. PLoS One 7, e45860.Google Scholar

  • Heil, F., Hemmi, H., Hochrein, H., Ampenberger, F., Kirschning, C., Akira, S., Lipford, G., Wagner, H., and Bauer, S. (2004). Species-specific recognition of single-stranded RNA via Toll-like receptor 7 and 8. Science 303, 1526–1529.Google Scholar

  • Hemmi, H., Takeuchi, O., Kawai, T., Kaisho, T., Sato, S., Sanjo, H., Matsumoto, M., Hoshino, K., Wagner, H., Takeda, K., et al. (2000), A Toll-like receptor recognizes bacterial DNA. Nature 408, 740–745.Google Scholar

  • Hemmi, H., Kaisho, T., Takeuchi, O., Sato, S., Sanjo, H., Hoshino, K., Horiuchi, T., Tomizawa, H., Takeda, K., and Akira, S. (2002). Small anti-viral compounds activate immune cells via the TLR7 MyD88-dependent signaling pathway. Nat. Immunol. 3, 196–200.CrossrefGoogle Scholar

  • Henneke, P., Takeuchi O., van Strijp, J.A., Guttormsen, H.K., Smith, J.A., Schromm, A.B., Espevik, T.A., Akira, S., Nizet, V., Kasper, D.L., et al. (2001). Novel engagement of CD14 and multiple Toll-like receptors by group B streptococci. J. Immunol. 167, 7069–7076.Google Scholar

  • Hennessy, E.J., Parker, A.E., and O’Neill, L.A. (2010). Targeting Toll-like receptors: emerging therapeutics? Nat. Rev. Drug Discov. 9, 293–307.CrossrefGoogle Scholar

  • Henrick, B.M., Nag, K., Yao, X.D., Drannik, A.G., Aldrovandi, G.M., and Rosenthal, K.L. (2012). Milk matters: soluble Toll-like receptor 2 (sTLR2) in breast milk significantly inhibits HIV-1 infection and inflammation. PLoS One 7, e40138.Google Scholar

  • Herrmann, I., Kellert, M., Schmidt, H., Mildner, A., Hanisch, U.K., Brück, W., Prinz, M., and Nau, R. (2006). Streptococcus pneumoniae Infection aggravates experimental autoimmune encephalomyelitis via Toll-like receptor 2. Infect. Immun. 74, 4841–4848.CrossrefGoogle Scholar

  • Hertz, C.J., Wu, Q., Porter, E.M., Zhang, Y.J., Weismüller, K.H., Godowski, P.J., Ganz, T., Randell, S.H., and Modlin, R.L. (2003). Activation of Toll-like receptor 2 on human tracheobronchial epithelial cells induces the antimicrobial peptide human β defensin-2. J. Immunol. 171, 6820–6826.Google Scholar

  • Hirschfeld, M., Weis, J.J., Toshchakov, V., Salkowski, C.A., Cody, M.J., Ward, D.C., Qureshi, N., Michalek, S.M., and Vogel, S.N. (2001). Signaling by Toll-like receptor 2 and 4 agonists results in differential gene expression in murine macrophages. Infect. Immun. 69, 1477–1482.Google Scholar

  • Hodgkinson, L. (2010). Digestive Disease Week 2010. Turning science into medicine – part 2. IDrugs 13, 424–426.PubMedGoogle Scholar

  • Holley, M.M., Zhang, Y., Lehrmann, E., Wood, W.H., Becker, K.G., and Kielian, T. (2012). Toll-like receptor 2 (TLR2)-TLR9 crosstalk dictates IL-12 family cytokine production in microglia. Glia 60, 29–42.CrossrefGoogle Scholar

  • Horng, T., Barton, G.M., and Medzhitov, R. (2001). TIRAP: an adapter molecule in the Toll signaling pathway. Nat. Immunol. 2, 835–841.PubMedCrossrefGoogle Scholar

  • Ireland, D.D., Stohlman, S.A., Hinton, D.R., Kapil, P., Silverman, R.H., Atkinson, R.A., and Bergmann, C.C. (2009). RNase L mediated protection from virus induced demyelination. PLoS Pathog. 5, e1000602.CrossrefGoogle Scholar

  • Iwamura, C. and Nakayama, T. (2008). Toll-like receptors in the respiratory system: their roles in inflammation. Curr. Allergy Asthma Rep. 8, 7–13.Google Scholar

  • Iyer, S., Kontoyiannis, D., Chevrier, D., Woo, J., Mori, N., Cornejo, M., Kollias, G., and Buelow R. (2000). Inhibition of tumor necrosis factor mRNA translation by a rationally designed immunomodulatory peptide. J. Biol. Chem. 275, 17051–17057.Google Scholar

  • Jack, C.S., Arbour, N., Manusow, J., Montgrain, V., Blain, M., McCrea, E., Shapiro, A., and Antel, J.P. (2005). TLR signaling tailors innate immune responses in human microglia and astrocytes. J. Immunol. 175, 4320–4330.Google Scholar

  • Jack, C.S., Arbour, N., Blain, M., Meier, U.C., Prat, A., and Antel, J.P. (2007). Th1 polarization of CD4+ T cells by Toll-like receptor 3-activated human microglia. J. Neuropathol. Exp. Neurol. 66, 848–859.Google Scholar

  • Jakovac, H., Grebic, D., Barac-Latas, V., Mrakovcic, I., and Radosevic-Stasic, B. (2013). Expression pattern of the endoplasmic reticulum stress protein gp96 in monophasic and chronic relapsing form of experimental autoimmune encephalomyelitis in rats. Histol. Histopathol. 28, 61–78.Google Scholar

  • Jasani, B., Navabi, H., and Adams, M. (2009). Ampligen: a potential Toll-like 3 receptor adjuvant for immunotherapy of cancer. Vaccine 27, 3401–3404.Google Scholar

  • Jeannin, P., Renno, T., Goetsch, L., Miconnet, I., Aubry, J.P., Delneste, Y., Herbault, N., Baussant, T., Magistrelli, G., Soulas, C., et al. (2000). OmpA targets dendritic cells, induces their maturation and delivers antigen into the MHC class I presentation pathway. Nat. Immunol. 1, 502–509.Google Scholar

  • Jenkins, K.A. and Mansell, A. (2010). TIR-containing adaptors in Toll-like receptor signalling. Cytokine 49, 237–244.Google Scholar

  • Jeong, E. and Lee, J.Y. (2011). Intrinsic and extrinsic regulation of innate immune receptors. Yonsei Med. J. 52, 379–392.CrossrefPubMedGoogle Scholar

  • Jeyaseelan, S., Manzer, R., Young, S.K., Yamamoto, M., Akira, S., Mason, R.J., and Worthen, G.S. (2005). Toll-IL-1 receptor domain-containing adaptor protein is critical for early lung immune responses against Escherichia coli lipopolysaccharide and viable Escherichia coli. J. Immunol. 175, 7484–7495.Google Scholar

  • Jiang, D., Liang, J., Fan, J., Yu, S., Chen, S., Luo, Y., Prestwich, G.D., Mascarenhas, M.M., Garg, H.G., Quinn, D.A., et al. (2005). Regulation of lung injury and repair by Toll-like receptors and hyaluronan. Nat. Med. 11, 1173–1179.CrossrefPubMedGoogle Scholar

  • Jin, M.S. and Lee, J.O. (2008). Structures of the Toll-like receptor family and its ligand complexes. Immunity 29, 182–191.PubMedCrossrefGoogle Scholar

  • Johnson, G.B., Brunn, G.J., Kodaira, Y., and Platt, J.L. (2002). Receptor-mediated monitoring of tissue well-being via detection of soluble heparan sulfate by Toll-like receptor 4. J. Immunol. 168, 5233–5239.Google Scholar

  • Johnson, A.J., Suidan, G.L., McDole, J., and Pirko I. (2007). The CD8 T cell in multiple sclerosis: suppressor cell or mediator of neuropathology? Int. Rev. Neurobiol. 79, 73–97.CrossrefGoogle Scholar

  • Johnson, T.P., Tyagi, R., Patel, K., Schiess, N., Calabresi, P.A., and Nath, A. (2013). Impaired Toll-like receptor 8 signaling in multiple sclerosis. J. Neuroinflammation 10, 74.CrossrefGoogle Scholar

  • Jones, S.W., Christison, R., Bundell, K., Voyce, C.J., Brockbank, S.M., Newham, P., and Lindsay, M.A. (2005). Characterisation of cell-penetrating peptide-mediated peptide delivery. Br. J. Pharmacol. 145, 1093–1102.Google Scholar

  • Jurk, M., Heil, F., Vollmer, J., Schetter, C., Krieg, A.M., Wagner, H., Lipford, G., and Bauer, S. (2002). Human TLR7 or TLR8 independently confer responsiveness to the antiviral compound R-848. Nat. Immunol. 3, 499.Google Scholar

  • Kabeya, Y., Kawamata, T., Suzuki, K., and Ohsumi, Y. (2007). Cis1/Atg31 is required for autophagosome formation in Saccharomyces cerevisiae. Biochem. Biophys. Res. Commun. 356, 405–410.Google Scholar

  • Kaisho, T. and Akira, S. (2003). Regulation of dendritic cell function through Toll-like receptors. Curr. Mol. Med. 3, 373–385.PubMedCrossrefGoogle Scholar

  • Kaisho, T. and Akira, S. (2006). Toll-like receptor function and signaling. J. Allergy Clin. Immunol. 117, 979–987; quiz 988.Google Scholar

  • Kariko, K., Ni, H., Capodici, J., Lamphier, M., and Weissman, D. (2004). mRNA is an endogenous ligand for Toll-like receptor 3. J. Biol. Chem. 279, 12542–12550.Google Scholar

  • Kawai, T. and Akira, S. (2006). TLR signaling. Cell Death Differ. 13, 816–825.PubMedGoogle Scholar

  • Kawai, T. and Akira, S. (2009). The roles of TLRs, RLRs and NLRs in pathogen recognition. Int. Immunol. 21, 317–337.PubMedCrossrefGoogle Scholar

  • Kawai, T. and Akira, S. (2010). The role of pattern-recognition receptors in innate immunity: update on Toll-like receptors. Nat. Immunol. 11, 373–384.PubMedCrossrefGoogle Scholar

  • Kawasaki, K., Akashi, S., Shimazu, R., Yoshida, T., Miyake, K., and Nishijima, M. (2000). Mouse Toll-like receptor 4.MD-2 complex mediates lipopolysaccharide-mimetic signal transduction by Taxol. J. Biol. Chem. 275, 2251–2254.Google Scholar

  • Kawata, T., Bristol, J.R., Rossignol, D.P., Rose, J.R., Kobayashi, S., Yokohama, H., Ishibashi, A., Christ, W.J., Katayama, K., Yamatsu, I., et al. (1999). E5531, a synthetic non-toxic lipid A derivative blocks the immunobiological activities of lipopolysaccharide. Br. J. Pharmacol. 127, 853–862.Google Scholar

  • Kenny, E.F. and O’Neill, L.A. (2008). Signalling adaptors used by Toll-like receptors: an update. Cytokine 43, 342–349.CrossrefGoogle Scholar

  • Keogh, B. and Parker, A.E. (2011). Toll-like receptors as targets for immune disorders. Trends Pharmacol. Sci. 32, 435–442.PubMedCrossrefGoogle Scholar

  • Kerfoot, S.M., Long, E.M., Hickey, M.J., Andonegui, G., Lapointe, B.M., Zanardo, R.C., Bonder, C., James, W.G., Robbins, S.M., and Kubes, P. (2004). TLR4 contributes to disease-inducing mechanisms resulting in central nervous system autoimmune disease. J. Immunol. 173, 7070–7077.Google Scholar

  • Khuda, I.I., Koide, N., Noman, A.S., Dagvadorj, J., Tumurkhuu, G., Naiki, Y., Komatsu, T., Yoshida, T., and Yokochi, T. (2009). Astrocyte elevated gene-1 (AEG-1) is induced by lipopolysaccharide as Toll-like receptor 4 (TLR4) ligand and regulates TLR4 signalling. Immunology 128, e700–e706.Google Scholar

  • Kinjyo, I., Hanada, T., Inagaki-Ohara, K., Mori, H., Aki, D., Ohishi, M., Yoshida, H., Kubo, M., and Yoshimura, A. (2002). SOCS1/JAB is a negative regulator of LPS-induced macrophage activation. Immunity 17, 583–591.CrossrefGoogle Scholar

  • Kleinman, M.E., Yamada, K., Takeda, A., Chandrasekaran, V., Nozaki, M., Baffi, J.Z., Albuquerque, R.J., Yamasaki, S., Itaya, M., Pan, Y., et al. (2008). Sequence- and target-independent angiogenesis suppression by siRNA via TLR3. Nature 452, 591–597.Google Scholar

  • Koenigsknecht-Talboo, J. and Landreth, G.E. (2005). Microglial phagocytosis induced by fibrillar beta-amyloid and IgGs are differentially regulated by proinflammatory cytokines. J. Neurosci. 25, 8240–8249.CrossrefGoogle Scholar

  • Kraft, A.D. and Harry, G.J. (2011). Features of microglia and neuroinflammation relevant to environmental exposure and neurotoxicity. Int. J. Environ. Res. Public Health 8, 2980–3018.PubMedCrossrefGoogle Scholar

  • Kreutzberg, G.W. (1996). Microglia: a sensor for pathological events in the CNS. Trends Neurosci. 19, 312–318.CrossrefPubMedGoogle Scholar

  • Krieg, A.M. (2003). CpG motifs: the active ingredient in bacterial extracts? Nat. Med. 9, 831–835.CrossrefPubMedGoogle Scholar

  • Kumar, S., Patel, R., Moore, S., Crawford, D.K., Suwanna, N., Mangiardi, M., and Tiwari-Woodruff, S.K. (2013). Estrogen receptor beta ligand therapy activates PI3K/Akt/mTOR signaling in oligodendrocytes and promotes remyelination in a mouse model of multiple sclerosis. Neurobiol. Dis. 56, 131–144.CrossrefGoogle Scholar

  • Kurt-Jones, E.A., Popova, L., Kwinn, L., Haynes, L.M., Jones, L.P., Tripp, R.A., Walsh, E.E., Freeman, M.W., Golenbock, D.T., Anderson, L.J., et al. (2000). Pattern recognition receptors TLR4 and CD14 mediate response to respiratory syncytial virus. Nat. Immunol. 1, 398–401.Google Scholar

  • Kurtzke, J.F. (2000). Multiple sclerosis in time and space – geographic clues to cause. J. Neurovirol. 6, S134–S140.Google Scholar

  • Kutzelnigg, A., Lucchinetti, C.F., Stadelmann, C., Brück, W., Rauschka, H., Bergmann, M., Schmidbauer, M., Parisi, J.E., and Lassmann, H. (2005). Cortical demyelination and diffuse white matter injury in multiple sclerosis. Brain 128, 2705–2712.Google Scholar

  • Lampropoulou, V., Hoehlig, K., Roch, T., Neves, P., Calderón Gómez, E., Sweenie, C.H., Hao, Y., Freitas, A.A., Steinhoff, U., Anderton, S.M., et al. (2008). TLR-activated B cells suppress T cell-mediated autoimmunity. J. Immunol. 180, 4763–4773.CrossrefGoogle Scholar

  • Lampropoulou, V., Calderon-Gomez, E., Roch, T., Neves, P., Shen, P., Stervbo, U., Boudinot, P., Anderton, S.M., and Fillatreau, S. (2010). Suppressive functions of activated B cells in autoimmune diseases reveal the dual roles of Toll-like receptors in immunity. Immunol. Rev. 233, 146–161.Google Scholar

  • Lassmann, H. (2008). Mechanisms of inflammation induced tissue injury in multiple sclerosis. J. Neurol. Sci. 274, 45–47.Google Scholar

  • Leadbetter, E.A., Rifkin, I.R., Hohlbaum, A.M., Beaudette, B.C., Shlomchik, M.J., and Marshak-Rothstein, A. (2002). Chromatin-IgG complexes activate B cells by dual engagement of IgM and Toll-like receptors. Nature 416, 603–607.Google Scholar

  • LeBouder, E., Rey-Nores, J.E., Rushmere, N.K., Grigorov, M., Lawn, S.D., Affolter, M., Griffin, G.E., Ferrara, P., Schiffrin, E.J., Morgan, B.P., et al. (2003). Soluble forms of Toll-like receptor (TLR)2 capable of modulating TLR2 signaling are present in human plasma and breast milk. J. Immunol. 171, 6680–6689.Google Scholar

  • Ledeboer, A., Hutchinson, M.R., Watkins, L.R., and Johnson, K.W. (2007). Ibudilast (AV-411). A new class therapeutic candidate for neuropathic pain and opioid withdrawal syndromes. Expert Opin. Investig. Drugs 16, 935–950.CrossrefGoogle Scholar

  • Lee, S.J. and Lee, S. (2002). Toll-like receptors and inflammation in the CNS. Curr Drug Targets Inflamm Allergy 1, 181–191.PubMedGoogle Scholar

  • Lee, J., Chuang, T.H., Redecke, V., She, L., Pitha, P.M., Carson, D.A., Raz, E., and Cottam, H.B. (2003). Molecular basis for the immunostimulatory activity of guanine nucleoside analogs: activation of Toll-like receptor 7. Proc. Natl. Acad. Sci. USA 100, 6646–6651.CrossrefGoogle Scholar

  • Lee, J.S., Lee, J.Y., Lee, M.Y., Hwang, D.H., and Youn, H.S. (2008). Acrolein with an alpha, beta-unsaturated carbonyl group inhibits LPS-induced homodimerization of Toll-like receptor 4. Mol. Cells 25, 253–257.PubMedGoogle Scholar

  • Lehnardt, S., Lachance, C., Patrizi, S., Lefebvre, S., Follett, P.L., Jensen, F.E., Rosenberg, P.A., Volpe, J.J., and Vartanian, T. (2002). The Toll-like receptor TLR4 is necessary for lipopolysaccharide-induced oligodendrocyte injury in the CNS. J. Neurosci. 22, 2478–2486.Google Scholar

  • Lehnardt, S., Massillon, L., Follett, P., Jensen, F.E., Ratan, R., Rosenberg, P.A., Volpe, J.J., and Vartanian, T. (2003). Activation of innate immunity in the CNS triggers neurodegeneration through a Toll-like receptor 4-dependent pathway. Proc. Natl. Acad. Sci. USA 100, 8514–8519.CrossrefGoogle Scholar

  • Leissring, M.A. (2008). The AbetaCs of Abeta-cleaving proteases. J. Biol. Chem. 283, 29645–29649.Google Scholar

  • Li, Y., Chu, N., Hu, A., Gran, B., Rostami, A., and Zhang, G.X. (2007). Increased IL-23p19 expression in multiple sclerosis lesions and its induction in microglia. Brain 130, 490–501.Google Scholar

  • Li, F., Thiele, I., Jamshidi, N., and Palsson, B.Ø. (2009a). Identification of potential pathway mediation targets in Toll-like receptor signaling. PLoS Comput. Biol. 5, e1000292.CrossrefGoogle Scholar

  • Li, M., Chen, Q., Shen, Y., and Liu, W. (2009b). Candida albicans phospholipomannan triggers inflammatory responses of human keratinocytes through Toll-like receptor 2. Exp. Dermatol. 18, 603–610.Google Scholar

  • Li, G., Liang, X., and Lotze, M.T. (2013). HMGB1: the central cytokine for all lymphoid cells. Front. Immunol. 4, 68.Google Scholar

  • Liang, S.L., Quirk, D., and Zhou, A. (2006). RNase L: its biological roles and regulation. IUBMB Life 58, 508–514.PubMedCrossrefGoogle Scholar

  • Liew, F.Y., Xu, D., Brint, E.K., and O’Neill, L.A. (2005). Negative regulation of Toll-like receptor-mediated immune responses. Nat. Rev. Immunol. 5, 446–458.CrossrefGoogle Scholar

  • Lin, Y. and Wen, L. (2013). Inflammatory response following diffuse axonal injury. Int. J. Med. Sci. 10, 515–521.CrossrefPubMedGoogle Scholar

  • Linker, R.A., Reinhardt, M., Bendszus, M., Ladewig, G., Briel, A., Schirner, M., Mäurer, M., and Hauff, P. (2005). In vivo molecular imaging of adhesion molecules in experimental autoimmune encephalomyelitis (EAE). J. Autoimmun. 25, 199–205.CrossrefGoogle Scholar

  • Lipford, G., Forsbach, A., Zepp, C., Nguyen, T., Weeratna, R., McCluskie, M., Vollmer, J., Davis, H., and Krieg, A.M. (2007). Selective Toll-like Receptor 7/8/9 Antagonists for the Oral Treatment of Autoimmune Diseases. American College of Rheumatology, Annual scientific meeting.Google Scholar

  • Liu, X., Ukai, T., Yumoto, H., Davey, M., Goswami, S., Gibson, F.C. 3rd, and Genco, C.A. (2008). Toll-like receptor 2 plays a critical role in the progression of atherosclerosis that is independent of dietary lipids. Atherosclerosis 196, 146–154.Google Scholar

  • Liu-Bryan, R., Scott, P., Sydlaske, A., Rose, D.M., and Terkeltaub, R. (2005). Innate immunity conferred by Toll-like receptors 2 and 4 and myeloid differentiation factor 88 expression is pivotal to monosodium urate monohydrate crystal-induced inflammation. Arthritis Rheum. 52, 2936–2946.Google Scholar

  • Loiarro, M., Capolunghi, F., Fantò, N., Gallo, G., Campo, S., Arseni, B., Carsetti, R., Carminati, P., De Santis, R., Ruggiero, V., et al. (2007). Pivotal advance: inhibition of MyD88 dimerization and recruitment of IRAK1 and IRAK4 by a novel peptidomimetic compound. J. Leukoc. Biol. 82, 801–810.Google Scholar

  • Loiarro, M., Ruggiero, V., and Sette, C. (2010). Targeting TLR/IL-1R signalling in human diseases. Mediators Inflamm. 2010, 674363.Google Scholar

  • Loo, Y.M. and Gale, M., Jr. (2011). Immune signaling by RIG-I-like receptors. Immunity 34, 680–692.PubMedCrossrefGoogle Scholar

  • Lubbad, A., Oriowo, M.A., and Khan, I. (2009). Curcumin attenuates inflammation through inhibition of TLR-4 receptor in experimental colitis. Mol. Cell. Biochem. 322, 127–135.Google Scholar

  • Macfarlane, D.E. and Manzel, L. (1998). Antagonism of immunostimulatory CpG-oligodeoxynucleotides by quinacrine, chloroquine, and structurally related compounds. J. Immunol. 160, 1122–1131.Google Scholar

  • Maitra, U., Davis, S., Reilly, C.M., and Li, L. (2009). Differential regulation of Foxp3 and IL-17 expression in CD4 T helper cells by IRAK-1. J. Immunol. 182, 5763–5769.Google Scholar

  • Mancek-Keber, M. and Jerala, R. (2006). Structural similarity between the hydrophobic fluorescent probe and lipid A as a ligand of MD-2. FASEB. J. 20, 1836–1842.CrossrefGoogle Scholar

  • Mantovani, A., Sozzani, S., Locati, M., Allavena, P., and Sica, A. (2002). Macrophage polarization: tumor-associated macrophages as a paradigm for polarized M2 mononuclear phagocytes. Trends Immunol. 23, 549–555.CrossrefGoogle Scholar

  • Marshak-Rothstein, A. (2006). Toll-like receptors in systemic autoimmune disease. Nat. Rev. Immunol. 6, 823–835.CrossrefGoogle Scholar

  • Marta, M. (2009). Toll-like receptors in multiple sclerosis mouse experimental models. Ann. NY Acad. Sci. 1173, 458–462.Google Scholar

  • Marta, M., Andersson, A., Isaksson, M., Kämpe, O., and Lobell, A. (2008). Unexpected regulatory roles of TLR4 and TLR9 in experimental autoimmune encephalomyelitis. Eur. J. Immunol. 38, 565–575.CrossrefGoogle Scholar

  • Massari, P., Henneke, P., Ho, Y., Latz, E., Golenbock, D.T., and Wetzler, L.M. (2002). Cutting edge: immune stimulation by neisserial porins is Toll-like receptor 2 and MyD88 dependent. J. Immunol. 168, 1533–1537.CrossrefGoogle Scholar

  • Matsumoto, M. and Seya, T. (2008). TLR3: interferon induction by double-stranded RNA including poly(I:C). Adv. Drug Deliv. Rev. 60, 805–812.CrossrefGoogle Scholar

  • Means, T.K., Wang, S., Lien, E., Yoshimura, A., Golenbock, D.T., and Fenton, M.J. (1999). Human Toll-like receptors mediate cellular activation by Mycobacterium tuberculosis. J. Immunol. 163, 3920–3927.Google Scholar

  • Mellanby, R.J., Cambrook, H., Turner, D.G., O’Connor, R.A., Leech, M.D., Kurschus, F.C., MacDonald, A.S., Arnold, B., and Anderton, S.M. (2012). TLR-4 ligation of dendritic cells is sufficient to drive pathogenic T cell function in experimental autoimmune encephalomyelitis. J. Neuroinflammation 9, 248.CrossrefGoogle Scholar

  • Miggin, S.M. and O’Neill, L.A. (2006). New insights into the regulation of TLR signaling. J. Leukoc. Biol. 80, 220–226.Google Scholar

  • Mitsuzawa, H., Nishitani, C., Hyakushima, N., Shimizu, T., Sano, H., Matsushima, N., Fukase, K., and Kuroki, Y. (2006). Recombinant soluble forms of extracellular TLR4 domain and MD-2 inhibit lipopolysaccharide binding on cell surface and dampen lipopolysaccharide-induced pulmonary inflammation in mice. J. Immunol. 177, 8133–8139.Google Scholar

  • Miyake, K. (2007). Innate immune sensing of pathogens and danger signals by cell surface Toll-like receptors. Semin. Immunol. 19, 3–10.PubMedCrossrefGoogle Scholar

  • Monie, T.P., Gay, N.J., and Gangloff, M. (2009). Bioinformatic analysis of Toll-like receptor sequences and structures. Methods Mol. Biol. 517, 69–79.Google Scholar

  • Mujtaba, M.G., Flowers, L.O., Patel, C.B., Patel, R.A., Haider, M.I., Johnson, H.M. (2005). Treatment of mice with the suppressor of cytokine signaling-1 mimetic peptide, tyrosine kinase inhibitor peptide, prevents development of the acute form of experimental allergic encephalomyelitis and induces stable remission in the chronic relapsing/remitting form. J. Immunol. 175, 5077–5086.Google Scholar

  • Mullarkey, M., Rose, J.R., Bristol, J., Kawata, T., Kimura, A., Kobayashi, S., Przetak, M., Chow, J., Gusovsky, F., Christ, W.J., et al. (2003). Inhibition of endotoxin response by e5564, a novel Toll-like receptor 4-directed endotoxin antagonist. J. Pharmacol. Exp. Ther. 304, 1093–1102.Google Scholar

  • Napoli, I. and Neumann, H. (2009). Microglial clearance function in health and disease. Neuroscience 158, 1030–1038.Google Scholar

  • Napoli, I. and Neumann, H. (2010). Protective effects of microglia in multiple sclerosis. Exp. Neurol. 225, 24–28.Google Scholar

  • Nicodemus, C.F., Wang, L., Lucas, J., Varghese, B., and Berek, J.S. (2010). Toll-like receptor-3 as a target to enhance bioactivity of cancer immunotherapy. Am. J. Obstet. Gynecol. 202, 608.e1–608.e8.Google Scholar

  • Nikbin, B., Bonab, M.M., Khosravi, F., and Talebian, F. (2007). Role of B cells in pathogenesis of multiple sclerosis. Int. Rev. Neurobiol. 79, 13–42.CrossrefPubMedGoogle Scholar

  • O’Neill, L.A. (2006). Targeting signal transduction as a strategy to treat inflammatory diseases. Nat. Rev. Drug Discov. 5, 549–563.CrossrefGoogle Scholar

  • O’Neill, L.A. and Bowie, A.G. (2007). The family of five: TIR-domain-containing adaptors in Toll-like receptor signalling. Nat. Rev. Immunol. 7, 353–364.CrossrefGoogle Scholar

  • Ohno, K., Suzumura, A., Sawada, M., and Marunouchi, T. (1990). Production of granulocyte/macrophage colony-stimulating factor by cultured astrocytes. Biochem. Biophys. Res. Commun. 169, 719–724.Google Scholar

  • Okun, E., Griffioen, K.J., Lathia, J.D., Tang, S.C., Mattson, M.P., and Arumugam, T.V. (2009). Toll-like receptors in neurodegeneration. Brain. Res. Rev. 59, 278–292.CrossrefPubMedGoogle Scholar

  • Oliveira, A.C., Peixoto, J.R., de Arruda, L.B., Campos, M.A., Gazzinelli, R.T., Golenbock, D.T., Akira, S., Previato, J.O., Mendonça-Previato, L., Nobrega, A., et al. (2004). Expression of functional TLR4 confers proinflammatory responsiveness to Trypanosoma cruzi glycoinositolphospholipids and higher resistance to infection with T. cruzi. J. Immunol. 173, 5688–5696.Google Scholar

  • Olson, J.K. and Miller, S.D. (2004). Microglia initiate central nervous system innate and adaptive immune responses through multiple TLRs. J. Immunol. 173, 3916–3924.Google Scholar

  • Olson, J.K., Girvin, A.M., and Miller, S.D. (2001). Direct activation of innate and antigen-presenting functions of microglia following infection with Theiler’s virus. J. Virol. 75, 9780–9789.CrossrefGoogle Scholar

  • Opitz, B., Schröder, N.W., Spreitzer, I., Michelsen, K.S., Kirschning, C.J., Hallatschek, W., Zähringer, U., Hartung, T., Göbel, U.B., and Schumann, R.R. (2001). Toll-like receptor-2 mediates Treponema glycolipid and lipoteichoic acid-induced NF-kappaB translocation. J. Biol. Chem. 276, 22041–22047.Google Scholar

  • Osorio, F. and Reis e Sousa, C. (2011). Myeloid C-type lectin receptors in pathogen recognition and host defense. Immunity 34, 651–664.CrossrefGoogle Scholar

  • Ousman, S.S. and Kubes, P. (2012). Immune surveillance in the central nervous system. Nat. Neurosci. 15, 1096–1101.CrossrefPubMedGoogle Scholar

  • Ozinsky, A., Underhill, D.M., Fontenot, J.D., Hajjar, A.M., Smith, K.D., Wilson, C.B., Schroeder, L., and Aderem, A. (2000). The repertoire for pattern recognition of pathogens by the innate immune system is defined by cooperation between Toll-like receptors. Proc. Natl. Acad. Sci. USA 97, 13766–13771.CrossrefGoogle Scholar

  • Pais, T.F., Figueiredo, C., Peixoto, R., Braz, M.H., and Chatterjee, S. (2008). Necrotic neurons enhance microglial neurotoxicity through induction of glutaminase by a MyD88-dependent pathway. J. Neuroinflammation 5, 43.CrossrefGoogle Scholar

  • Pan, L.N., Zhu, W., Li, C., Xu, X.L., Guo, L.J., and Lu, Q. (2012). Toll-like receptor 3 agonist poly I:C protects against simulated cerebral ischemia in vitro and in vivo. Acta Pharmacol. Sin. 33, 1246–1253.CrossrefGoogle Scholar

  • Panter, G., Kuznik, A., and Jerala, R. (2009). Therapeutic applications of nucleic acids as ligands for Toll-like receptors. Curr. Opin. Mol. Ther. 11, 133–145.PubMedGoogle Scholar

  • Parajuli, B., Sonobe, Y., Kawanokuchi, J., Doi, Y., Noda, M., Takeuchi, H., Mizuno, T., and Suzumura, A. (2012). GM-CSF increases LPS-induced production of proinflammatory mediators via upregulation of TLR4 and CD14 in murine microglia. J. Neuroinflammation 9, 268.CrossrefGoogle Scholar

  • Park, J.S., Svetkauskaite, D., He, Q., Kim, J.Y., Strassheim, D., Ishizaka, A., and Abraham, E. (2004). Involvement of Toll-like receptors 2 and 4 in cellular activation by high mobility group box 1 protein. J. Biol. Chem. 279, 7370–7377.Google Scholar

  • Park, J.S., Gamboni-Robertson, F., He, Q., Svetkauskaite, D., Kim, J.Y., Strassheim, D., Sohn, J.W., Yamada, S., Maruyama, I., Banerjee. A., et al. (2006). High mobility group box 1 protein interacts with multiple Toll-like receptors. Am. J. Physiol. Cell Physiol. 290, C917–C924.Google Scholar

  • Pawar, R.D., Ramanjaneyulu, A., Kulkarni, O.P., Lech, M., Segerer, S., and Anders, H.J. (2007). Inhibition of Toll-like receptor-7 (TLR-7) or TLR-7 plus TLR-9 attenuates glomerulonephritis and lung injury in experimental lupus. J. Am. Soc. Nephrol. 18, 1721–1731.CrossrefGoogle Scholar

  • Peri, F. and Piazza, M. (2012). Therapeutic targeting of innate immunity with Toll-like receptor 4 (TLR4) antagonists. Biotechnol. Adv. 30, 251–260.Google Scholar

  • Perron, H., Geny, C., Laurent, A., Mouriquand, C., Pellat, J., Perret, J., and Seigneurin, J.M. (1989). Leptomeningeal cell line from multiple sclerosis with reverse transcriptase activity and viral particles. Res. Virol. 140, 551–561.Google Scholar

  • Perron, H., Lalande, B., Gratacap, B., Laurent, A., Genoulaz, O., Geny, C., Mallaret, M., Schuller, E., Stoebner, P., and Seigneurin, J.M. (1991). Isolation of retrovirus from patients with multiple sclerosis. Lancet 337, 862–863.Google Scholar

  • Perron, H., Garson, J.A., Bedin, F., Beseme, F., Paranhos-Baccala, G., Komurian-Pradel, F., Mallet, F., Tuke, P.W., Voisset, C., Blond, J.L., et al. (1997). Molecular identification of a novel retrovirus repeatedly isolated from patients with multiple sclerosis. The Collaborative Research Group on Multiple Sclerosis. Proc. Natl. Acad. Sci. USA 94, 7583–7588.CrossrefGoogle Scholar

  • Perry, V.H., Anthony, D.C., Bolton, S.J., and Brown H.C. (1997). The blood-brain barrier and the inflammatory response. Mol. Med. Today 3, 335–341.CrossrefGoogle Scholar

  • Pisegna, S., Pirozzi, G., Piccoli, M., Frati, L., Santoni, A., and Palmieri, G. (2004). p38 MAPK activation controls the TLR3-mediated up-regulation of cytotoxicity and cytokine production in human NK cells. Blood 104, 4157–4164.CrossrefGoogle Scholar

  • Poltorak, A., He, X., Smirnova, I., Liu, M.Y., Van Huffel, C., Du, X., Birdwell, D., Alejos, E., Silva, M., Galanos, C., et al. (1998). Defective LPS signaling in C3H/HeJ and C57BL/10ScCr mice: mutations in Tlr4 gene. Science 282, 2085–2088.Google Scholar

  • Ponomarev, E.D., Shriver, L.P., Maresz, K., Pedras-Vasconcelos, J., Verthelyi, D., and Dittel, B.N. (2007). GM-CSF production by autoreactive T cells is required for the activation of microglial cells and the onset of experimental autoimmune encephalomyelitis. J. Immunol. 178, 39–48.Google Scholar

  • Prinz, M., Garbe, F., Schmidt, H., Mildner, A., Gutcher, I., Wolter, K., Piesche, M., Schroers, R., Weiss, E., Kirschning, C.J., et al. (2006). Innate immunity mediated by TLR9 modulates pathogenicity in an animal model of multiple sclerosis. J. Clin. Invest. 116, 456.CrossrefGoogle Scholar

  • Przetak, M., Chow, J., Cheng, H., Rose, J., Hawkins, L.D., and Ishizaka, S.T. (2003). Novel synthetic LPS receptor agonists boost systemic and mucosal antibody responses in mice. Vaccine 21, 961–970.PubMedCrossrefGoogle Scholar

  • Racke, M.K., Hu, W., and Lovett-Racke, A.E. (2005). PTX cruiser: driving autoimmunity via TLR4. Trends Immunol. 26, 289–291.CrossrefGoogle Scholar

  • Raivich, G. and Banati, R. (2004). Brain microglia and blood-derived macrophages: molecular profiles and functional roles in multiple sclerosis and animal models of autoimmune demyelinating disease. Brain Res. Brain. Res. Rev. 46, 261–281.PubMedCrossrefGoogle Scholar

  • Rasmussen, S., Wang, Y., Kivisäkk, P., Bronson, R.T., Meyer, M., Imitola, J., and Khoury, S.J. (2007). Persistent activation of microglia is associated with neuronal dysfunction of callosal projecting pathways and multiple sclerosis-like lesions in relapsing – remitting experimental autoimmune encephalomyelitis. Brain 130, 2816–2829.Google Scholar

  • Rasmussen, S.B., Reinert, L.S., and Paludan, S.R. (2009). Innate recognition of intracellular pathogens: detection and activation of the first line of defense. APMIS 117, 323–337.CrossrefPubMedGoogle Scholar

  • Rassa, J.C., Meyers, J.L., Zhang, Y., Kudaravalli, R., and Ross, S.R. (2002). Murine retroviruses activate B cells via interaction with Toll-like receptor 4. Proc. Natl. Acad. Sci. USA 99, 2281–2286.Google Scholar

  • Rezaei, N. (2006). Therapeutic targeting of pattern-recognition receptors. Int. Immunopharmacol. 6, 863–869.CrossrefPubMedGoogle Scholar

  • Robinson, R.A., DeVita, V.T., Levy, H.B., Baron, S., Hubbard, S.P., and Levine, A.S. (1976). A phase I–II trial of multiple-dose polyriboinosic-polyribocytidylic acid in patients with leukemia or solid tumors. J. Natl. Cancer Inst. 57, 599–602.Google Scholar

  • Rodríguez, D., Keller, A.C., Faquim-Mauro, E.L., de Macedo, M.S., Cunha, F.Q., Lefort, J., Vargaftig, B.B., and Russo, M. (2003). Bacterial lipopolysaccharide signaling through Toll-like receptor 4 suppresses asthma-like responses via nitric oxide synthase 2 activity. J. Immunol. 171, 1001–1008.Google Scholar

  • Roelofs, M.F., Boelens, W.C., Joosten, L.A., Abdollahi-Roodsaz, S., Geurts, J., Wunderink, L.U., Schreurs, B.W., van den Berg, W.B., and Radstake, T.R. (2006). Identification of small heat shock protein B8 (HSP22) as a novel TLR4 ligand and potential involvement in the pathogenesis of rheumatoid arthritis. J. Immunol. 176, 7021–7027.Google Scholar

  • Rolland, A., Jouvin-Marche, E., Viret, C., Faure, M., Perron, H., and Marche, P.N. (2006). The envelope protein of a human endogenous retrovirus-W family activates innate immunity through CD14/TLR4 and promotes Th1-like responses. J. Immunol. 176, 7636–7644.Google Scholar

  • Ruse, M. and Knaus, U.G. (2006). New players in TLR-mediated innate immunity: PI3K and small Rho GTPases. Immunol. Res. 34, 33–48.CrossrefGoogle Scholar

  • Sabroe, I. and Whyte, M.K. (2007). Toll-like receptor (TLR)-based networks regulate neutrophilic inflammation in respiratory disease. Biochem. Soc. Trans. 35, 1492–1495.CrossrefPubMedGoogle Scholar

  • Sadovnick, A.D. (2012). Genetic background of multiple sclerosis. Autoimmun. Rev. 11, 163–166.PubMedCrossrefGoogle Scholar

  • Schnare, M., Barton, G.M., Holt, A.C., Takeda, K., Akira, S., and Medzhitov, R. (2001). Toll-like receptors control activation of adaptive immune responses. Nat. Immunol. 2, 947–950.PubMedCrossrefGoogle Scholar

  • Schumann, R.R., Lamping, N., and Hoess, A. (1997). Interchangeable endotoxin-binding domains in proteins with opposite lipopolysaccharide-dependent activities. J. Immunol. 159, 5599–5605.Google Scholar

  • Schwandner, R., Dziarski, R., Wesche, H., Rothe, M., and Kirschning, C.J. (1999). Peptidoglycan- and lipoteichoic acid-induced cell activation is mediated by Toll-like receptor 2. J. Biol. Chem. 274, 17406–17409.Google Scholar

  • Shacka, J.J. and Roth, K.A. (2007). Cathepsin D deficiency and NCL/Batten disease: there’s more to death than apoptosis. Autophagy 3, 474–476.CrossrefPubMedGoogle Scholar

  • Shingai, M., Azuma, M., Ebihara, T., Sasai, M., Funami, K., Ayata, M., Ogura, H., Tsutsumi, H., Matsumoto, M., and Seya, T. (2008). Soluble G protein of respiratory syncytial virus inhibits Toll-like receptor 3/4-mediated IFN-beta induction. Int. Immunol. 20, 1169–1180.CrossrefPubMedGoogle Scholar

  • Sloane, J.A., Batt, C., Ma, Y., Harris, Z.M., Trapp, B., and Vartanian, T. (2010). Hyaluronan blocks oligodendrocyte progenitor maturation and remyelination through TLR2. Proc. Natl. Acad. Sci. USA 107, 11555–11560.Google Scholar

  • Smiley, S.T., King, J.A., and Hancock, W.W. (2001). Fibrinogen stimulates macrophage chemokine secretion through Toll-like receptor 4. J. Immunol. 167, 2887–2894.Google Scholar

  • Song, K.W., Talamas, F.X., Suttmann, R.T., Olson, P.S., Barnett, J.W., Lee, S.W., Thompson, K.D., Jin, S., Hekmat-Nejad, M., Cai, T.Z., et al., (2009). The kinase activities of interleukin-1 receptor associated kinase (IRAK)-1 and 4 are redundant in the control of inflammatory cytokine expression in human cells. Mol. Immunol. 46, 1458–1466.Google Scholar

  • Soulika, A.M., Lee, E., McCauley, E., Miers, L., Bannerman, P., and Pleasure, D. (2009). Initiation and progression of axonopathy in experimental autoimmune encephalomyelitis. J. Neurosci. 29, 14965–14979.CrossrefGoogle Scholar

  • Spiller, S., Elson, G., Ferstl, R., Dreher, S., Mueller, T., Freudenberg, M., Daubeuf, B., Wagner, H., and Kirschning, C.J. (2008). TLR4-induced IFN-gamma production increases TLR2 sensitivity and drives Gram-negative sepsis in mice. J. Exp. Med. 205, 1747–1754.Google Scholar

  • Stevens, M.F., Schwalbe, C.H., Patel, N., Gate, E.N., and Bryant, P.K. (1995). Structural studies on bioactive compounds. Part 26. Hydrogen bonding in the crystal structure of the N-methylformamide solvate of the immunomodulatory agent 2-amino-5-bromo-6-phenylpyrimidin-4-one (bropirimine): implications for the design of novel anti-tumour strategies. Anticancer Drug Des. 10, 203–213.Google Scholar

  • Strayer, D.R., Carter, W.A., Brodsky, I., Cheney, P., Peterson, D., Salvato, P., Thompson, C., Loveless, M., Shapiro, D.E., Elsasser, W., et al. (1994). A controlled clinical trial with a specifically configured RNA drug, poly(I).poly(C12U), in chronic fatigue syndrome. Clin. Infect. Dis. 18, S88–S95.Google Scholar

  • Stromnes, I.M. and Goverman, J.M. (2006a). Active induction of experimental allergic encephalomyelitis. Nat. Protoc. 1, 1810–1819.Google Scholar

  • Stromnes, I.M. and Goverman, J.M. (2006b). Passive induction of experimental allergic encephalomyelitis. Nat. Protoc. 1, 1952–1960.Google Scholar

  • Sugiyama, T., Hoshino, K., Saito, M., Yano, T., Sasaki, I., Yamazaki, C., Akira, S., and Kaisho, T. (2008). Immunoadjuvant effects of polyadenylic:polyuridylic acids through TLR3 and TLR7. Int. Immunol. 20, 1–9.Google Scholar

  • Suhadolnik, R.J., Reichenbach, N.L., Hitzges, P., Adelson, M.E., Peterson, D.L., Cheney, P., Salvato, P., Thompson, C., Loveless, M., Müller, W.E., et al. (1994). Changes in the 2-5A synthetase/RNase L antiviral pathway in a controlled clinical trial with poly(I)-poly(C12U) in chronic fatigue syndrome. In Vivo 8, 599–604.Google Scholar

  • Sun, S., Rao, N.L., Venable, J., Thurmond, R., and Karlsson, L. (2007). TLR7/9 antagonists as therapeutics for immune-mediated inflammatory disorders. Inflamm. Allergy Drug Targets 6, 223–235.Google Scholar

  • Sutmuller, R., Garritsen, A., and Adema, G.J. (2007). Regulatory T cells and Toll-like receptors: regulating the regulators. Ann. Rheum. Dis. 66, iii91–iii95.CrossrefGoogle Scholar

  • Suzuki, N., Suzuki, S., Millar, D.G., Unno, M., Hara, H., Calzascia, T., Yamasaki, S., Yokosuka, T., Chen, N.J., Elford, A.R., et al. (2006). A critical role for the innate immune signaling molecule IRAK-4 in T cell activation. Science 311, 1927–1932.Google Scholar

  • t Hart, B.A., Gran, B., and Weissert, R. (2011). EAE: imperfect but useful models of multiple sclerosis. Trends Mol. Med. 17, 119–125.CrossrefGoogle Scholar

  • Takashima, K., Matsunaga, N., Yoshimatsu, M., Hazeki, K., Kaisho, T., Uekata, M., Hazeki, O., Akira, S., Iizawa, Y., and Ii, M. (2009). Analysis of binding site for the novel small-molecule TLR4 signal transduction inhibitor TAK-242 and its therapeutic effect on mouse sepsis model. Br. J. Pharmacol. 157, 1250–1262.Google Scholar

  • Takeda, K., Kaisho, T., and Akira, S. (2003). Toll-like receptors. Annu. Rev. Immunol. 21, 335–376.PubMedCrossrefGoogle Scholar

  • Takeuchi, O., Kawai, T., Mühlradt, P.F., Morr, M., Radolf, J.D., Zychlinsky, A., Takeda, K., and Akira, S. (2001). Discrimination of bacterial lipoproteins by Toll-like receptor 6. Int. Immunol. 13, 933–940.CrossrefPubMedGoogle Scholar

  • Takeuchi, O., Sato, S., Horiuchi, T., Hoshino, K., Takeda, K., Dong, Z., Modlin, R.L., and Akira, S. (2002). Cutting edge: role of Toll-like receptor 1 in mediating immune response to microbial lipoproteins. J. Immunol. 169, 10–14.Google Scholar

  • Tang, S.C., Arumugam, T.V., Xu, X., Cheng, A., Mughal, M.R., Jo, D.G., Lathia, J.D., Siler, D.A., Chigurupati, S., Ouyang, X., et al. (2007). Pivotal role for neuronal Toll-like receptors in ischemic brain injury and functional deficits. Proc. Natl. Acad. Sci. USA 104, 13798–13803.CrossrefGoogle Scholar

  • Termeer, C., Benedix, F., Sleeman, J., Fieber, C., Voith, U., Ahrens, T., Miyake, K., Freudenberg, M., Galanos, C., and Simon, J.C. (2002). Oligosaccharides of Hyaluronan activate dendritic cells via Toll-like receptor 4. J. Exp. Med. 195, 99–111.Google Scholar

  • Toshchakov, V., Jones, B.W., Perera, P.Y., Thomas, K., Cody, M.J., Zhang, S., Williams, B.R., Major, J., Hamilton, T.A., Fenton, M.J., et al. (2002). TLR4, but not TLR2, mediates IFN-beta-induced STAT1alpha/beta-dependent gene expression in macrophages. Nat. Immunol. 3, 392–398.CrossrefGoogle Scholar

  • Toshchakov, V.U., Basu, S., Fenton, M.J., and Vogel, S.N. (2005). Differential involvement of BB loops of Toll-IL-1 resistance (TIR) domain-containing adapter proteins in TLR4- versus TLR2-mediated signal transduction. J. Immunol. 175, 494–500.Google Scholar

  • Toshchakov, V.Y., Fenton, M.J., and Vogel, S.N. (2007). Cutting edge: differential inhibition of TLR signaling pathways by cell-permeable peptides representing BB loops of TLRs. J. Immunol. 178, 2655–2660.Google Scholar

  • Touil, T., Fitzgerald, D., Zhang, G.X., Rostami, A., and Gran, B. (2006). Cutting edge: TLR3 stimulation suppresses experimental autoimmune encephalomyelitis by inducing endogenous IFN-β. J. Immunol. 177, 7505–7509.Google Scholar

  • Town, T., Jeng, D., Alexopoulou, L., Tan, J., and Flavell, R.A. (2006). Microglia recognize double-stranded RNA via TLR3. J. Immunol. 176, 3804–3812.Google Scholar

  • Trapp, B.D. and Nave, K.A. (2008). Multiple sclerosis: an immune or neurodegenerative disorder? Annu. Rev. Neurosci. 31, 247–269.CrossrefPubMedGoogle Scholar

  • Trapp, B.D. and Stys, P.K. (2009). Virtual hypoxia and chronic necrosis of demyelinated axons in multiple sclerosis. Lancet Neurol. 8, 280–291.PubMedCrossrefGoogle Scholar

  • Travis, S., Yap, L.M., Hawkey, C., Warren, B., Lazarov, M., Fong, T., Tesi, R.J.; RDP Investigators Study Group. (2005). RDP58 is a novel and potentially effective oral therapy for ulcerative colitis. Inflamm. Bowel Dis. 11, 713–719.CrossrefGoogle Scholar

  • Trieu, A., Roberts, T.L., Dunn, J.A., Sweet, M.J., and Stacey, K.J. (2006). DNA motifs suppressing TLR9 responses. Crit. Rev. Immunol. 26, 527–544.CrossrefGoogle Scholar

  • Tullman, M.J. (2013). A review of current and emerging therapeutic strategies in multiple sclerosis. Am. J. Manag. Care 19, S21–S27.Google Scholar

  • Ulevitch, R.J. (2004). Therapeutics targeting the innate immune system. Nat. Rev. Immunol. 4, 512–520.CrossrefPubMedGoogle Scholar

  • Underhill, D.M., Ozinsky, A., Hajjar, A.M., Stevens, A., Wilson, C.B., Bassetti, M., and Aderem, A. (1999). The Toll-like receptor 2 is recruited to macrophage phagosomes and discriminates between pathogens. Nature. 401, 811–815.Google Scholar

  • Ungaro, R., Fukata, M., Hsu, D., Hernandez, Y., Breglio, K., Chen, A., Xu, R., Sotolongo, J., Espana, C., Zaias, J., et al. (2009). A novel Toll-like receptor 4 antagonist antibody ameliorates inflammation but impairs mucosal healing in murine colitis. Am. J. Physiol. Gastrointest. Liver Physiol. 296, G1167–G1179.Google Scholar

  • Vabulas, R.M., Ahmad-Nejad, P., da Costa, C., Miethke, T., Kirschning, C.J., Häcker, H., and Wagner, H. (2001). Endocytosed HSP60s use Toll-like receptor 2 (TLR2) and TLR4 to activate the Toll/interleukin-1 receptor signaling pathway in innate immune cells. J. Biol. Chem. 276, 31332–31339.Google Scholar

  • Vabulas, R.M., Ahmad-Nejad, P., Ghose, S., Kirschning, C.J., Issels, R.D., and Wagner, H. (2002a). HSP70 as endogenous stimulus of the Toll/interleukin-1 receptor signal pathway. J. Biol. Chem. 277, 15107–15112.CrossrefGoogle Scholar

  • Vabulas, R.M., Braedel, S., Hilf, N., Singh-Jasuja, H., Herter, S., Ahmad-Nejad, P., Kirschning, C.J., Da Costa, C., Rammensee, H.G., Wagner, H., et al. (2002b). The endoplasmic reticulum-resident heat shock protein Gp96 activates dendritic cells via the Toll-like receptor 2/4 pathway. J. Biol. Chem. 277, 20847–20853.Google Scholar

  • Vaishnaw, A.K., Gollob, J., Gamba-Vitalo, C., Hutabarat, R., Sah, D., Meyers, R., de Fougerolles, T., and Maraganore, J. (2010). A status report on RNAi therapeutics. Silence 1, 14.Google Scholar

  • Van Bockstaele, F., Holz, J.B., and Revets, H. (2009). The development of nanobodies for therapeutic applications. Curr. Opin. Investig. Drugs (London, England: 2000) 10, 1212–1224.Google Scholar

  • Van Tassell, B.W., Seropian, I.M., Toldo, S., Salloum, F.N., Smithson, L., Varma, A., Hoke, N.N., Gelwix, C., Chau, V., and Abbate, A. (2010). Pharmacologic inhibition of myeloid differentiation factor 88 (MyD88) prevents left ventricular dilation and hypertrophy after experimental acute myocardial infarction in the mouse. J. Cardiovasc. Pharmacol. 55, 385–390.CrossrefGoogle Scholar

  • Visser, L., Jan de Heer, H., Boven, L.A., van Riel, D., van Meurs, M., Melief, M.J., Zähringer, U., van Strijp, J., Lambrecht, B.N., Nieuwenhuis, E.E., et al. (2005). Proinflammatory bacterial peptidoglycan as a cofactor for the development of central nervous system autoimmune disease. J. Immunol. 174, 808–816.Google Scholar

  • Visser, L., Melief, M.J., van Riel, D., van Meurs, M., Sick, E.A., Inamura, S., Bajramovic, J.J., Amor, S., Hintzen, R.Q., Boven, L.A., et al. (2006). Phagocytes containing a disease-promoting Toll-like receptor/Nod ligand are present in the brain during demyelinating disease in primates. Am. J. Pathol. 169, 1671–1685.Google Scholar

  • Vogel, S.N., Fitzgerald, K.A., and Fenton, M.J. (2003). TLRs: differential adapter utilization by Toll-like receptors mediates TLR-specific patterns of gene expression. Mol. Interv. 3, 466–477.PubMedCrossrefGoogle Scholar

  • Vollmer, J., Tluk, S., Schmitz, C., Hamm, S., Jurk, M., Forsbach, A., Akira, S., Kelly, K.M., Reeves, W.H., Bauer, S., et al. (2005). Immune stimulation mediated by autoantigen binding sites within small nuclear RNAs involves Toll-like receptors 7 and 8. J. Exp. Med. 202, 1575–1585.Google Scholar

  • Waldner, H., Collins, M., and Kuchroo, V.K. (2004). Activation of antigen-presenting cells by microbial products breaks self tolerance and induces autoimmune disease. J. Clin. Invest. 113, 990–997.Google Scholar

  • Wang, R., Town, T., Gokarn, V., Flavell, R.A., and Chandawarkar, R.Y. (2006). HSP70 enhances macrophage phagocytosis by interaction with lipid raft-associated TLR-7 and upregulating p38 MAPK and PI3K pathways. J. Surg. Res. 136, 58–69.Google Scholar

  • Warger, T., Hilf, N., Rechtsteiner, G., Haselmayer, P., Carrick, D.M., Jonuleit, H., von Landenberg, P., Rammensee, H.G., Nicchitta, C.V., Radsak, M.P., et al. (2006). Interaction of TLR2 and TLR4 ligands with the N-terminal domain of Gp96 amplifies innate and adaptive immune responses. J. Biol. Chem. 281, 22545–22553.Google Scholar

  • Weiner, H.L. (2004). Multiple sclerosis is an inflammatory T-cell-mediated autoimmune disease. Arch. Neurol. 61, 1613–1615.CrossrefPubMedGoogle Scholar

  • Weiner, H.L. (2008). A shift from adaptive to innate immunity: a potential mechanism of disease progression in multiple sclerosis. J. Neurol. 255, 3–11.Google Scholar

  • Weiner, H.L. (2009). The challenge of multiple sclerosis: how do we cure a chronic heterogeneous disease? Ann. Neurol. 65, 239–248.CrossrefGoogle Scholar

  • Werts, C., Tapping, R.I., Mathison, J.C., Chuang, T.H., Kravchenko, V., Saint Girons, I., Haake, D.A., Godowski, P.J., Hayashi, F., Ozinsky, A., et al. (2001). Leptospiral lipopolysaccharide activates cells through a TLR2-dependent mechanism. Nat. Immunol. 2, 346–352.CrossrefGoogle Scholar

  • Wolf, N.A., Amouzegar, T.K., and Swanborg, R.H. (2007). Synergistic interaction between Toll-like receptor agonists is required for induction of experimental autoimmune encephalomyelitis in Lewis rats. J. Neuroimmunol. 185, 115–122.Google Scholar

  • Wu, G.F. and Alvarez, E. (2011). The immunopathophysiology of multiple sclerosis. Neurol. Clin. 29, 257–278.CrossrefPubMedGoogle Scholar

  • Wyllie, D.H., Kiss-Toth, E., Visintin, A., Smith, S.C., Boussouf, S., Segal, D.M., Duff, G.W., and Dower, S.K. (2000). Evidence for an accessory protein function for Toll-like receptor 1 in anti-bacterial responses. J. Immunol. 165, 7125–7132.Google Scholar

  • Xu, J., Wagoner, G., Douglas, J.C., and Drew, P.D. (2013). beta-Lapachone ameliorization of experimental autoimmune encephalomyelitis. J. Neuroimmunol. 254, 46–54.Google Scholar

  • Yarovinsky, F., Zhang, D., Andersen, J.F., Bannenberg, G.L., Serhan, C.N., Hayden, M.S., Hieny, S., Sutterwala, F.S., Flavell, R.A., Ghosh, S., et al. (2005). TLR11 activation of dendritic cells by a protozoan profilin-like protein. Science 308, 1626–1629.Google Scholar

  • Yoshimoto, T. and Nakanishi, K. (2006). Roles of IL-18 in basophils and mast cells. Allergol. Int. 55, 105–113.CrossrefGoogle Scholar

  • Youn, H.S., Lee, J.K., Choi, Y.J., Saitoh, S.I., Miyake, K., Hwang, D.H., and Lee, J.Y., (2008). Cinnamaldehyde suppresses Toll-like receptor 4 activation mediated through the inhibition of receptor oligomerization. Biochem. Pharmacol. 75, 494–502.Google Scholar

  • Youn, H.S., Kim, Y.S., Park, Z.Y., Kim, S.Y., Choi, N.Y., Joung, S.M., Seo, J.A., Lim, K.M., Kwak, M.K., Hwang, D.H., et al. (2010). Sulforaphane suppresses oligomerization of TLR4 in a thiol-dependent manner. J. Immunol. 184, 411–419.Google Scholar

  • Zekki, H., Feinstein, D.L., and Rivest, S. (2006). The clinical course of experimental autoimmune encephalomyelitis is associated with a profound and sustained transcriptional activation of the genes encoding Toll-like receptor 2 and CD14 in the mouse CNS. Brain Pathol. 12, 308–319.CrossrefGoogle Scholar

  • Zelcer, N., Khanlou, N., Clare, R., Jiang, Q., Reed-Geaghan, E.G., Landreth, G.E., Vinters, H.V., and Tontonoz, P. (2007). Attenuation of neuroinflammation and Alzheimer’s disease pathology by liver x receptors. Proc. Natl. Acad. Sci. USA 104, 10601–10606.Google Scholar

  • Zhang, X., Jin, J., Tang, Y., Speer, D., Sujkowska, D., and Markovic-Plese, S. (2009). IFN-β1a inhibits the secretion of Th17-polarizing cytokines in human dendritic cells via TLR7 up-regulation. J. Immunol. 182, 3928–3936.Google Scholar

  • Zhou, H., Yu, M., Fukuda, K., Im, J., Yao, P., Cui, W., Bulek, K., Zepp, J., Wan, Y., Kim, T.W., et al. (2013). IRAK-M mediates Toll-like receptor/IL-1R-induced NF-κB activation and cytokine production. EMBO J. 32, 583–596.Google Scholar

About the article

Maziar Gooshe

Maziar Gooshe is a medical student of Tehran University of Medical Sciences with a broad and acute interest in the discovery of new pathways and underlying mechanis ms of human neurophysiology, having an interest in human reproductive medicine. Also, particularly enjoying collaboration with scientists from different disciplines to develop new skills and solve new challenges. He is already doing his study under the supervision of Dr. Nima Rezaei at the Research Center for Immunodeficiencies, while he is also getting some experiences at the Department of Toxicology and Pharmacology as well as the Experimental Medicine Research Center.

Amir Hossein Abdolghaffari

Amir Hossein Abdolghaffari is a Pharmacology PhD candidate at Tehran University of Medical Sciences, which has published 14 papers in international journals and contributed in 2 chapters of Encyclopedia of Toxicology from Elsevier. His research interest is in signaling and oxidative stress. He is already a researcher at the Department of Pharmacology and Toxicology as well as Institute of Medicinal Plants, ACECR.

Maria Elsa Gambuzza

Maria Elsa Gambuzza is the Rome Adjunct microbiology professor at Degree Course of Biotechnology, University of Messina, who is already doing the Control Authority at the Ministry of Health. She has Degree in Biology – Specialization in Microbiology and Virology – PhD in “Microbial Biotechnology” and in “Clinical Neuroscience”. She has already several publications on role of Toll-like receptors in Alzheimer’s disease and multiple sclerosis.

Nima Rezaei

Nima Rezaei took the degree in Medicine in 2002 from Tehran University of Medical Sciences, the MSc in Molecular and Gentic Medicine in 2006, and the PhD in Human Genetics and Clinical Immunology in 2009 from the University of Sheffield. He is now working in Tehran University of Medical Sciences as an academic faculty member and as the chief executive director of the Children’s Medical Center. He is also the Deputy President of Research Center for Immunodeficiencies. He has presented more than 300 lectures/posters in congresses/meetings and has published more than 380 articles in international scientific journals during the last decade.


Corresponding author: Nima Rezaei, Research Center for Immunodeficiencies, Children’s Medical Center, Tehran University of Medical Sciences, Tehran 14194, Iran, e-mail:


Received: 2014-03-29

Accepted: 2014-05-08

Published Online: 2014-06-07

Published in Print: 2014-10-01


Citation Information: Reviews in the Neurosciences, Volume 25, Issue 5, Pages 713–739, ISSN (Online) 2191-0200, ISSN (Print) 0334-1763, DOI: https://doi.org/10.1515/revneuro-2014-0026.

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