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A Clear and Present Danger: Endogenous Ligands of Toll-like Receptors

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Abstract

Neurologic disease promoted by microbial pathogens, sterile injury, or neurodegeneration rapidly induces innate immunity in adjacent healthy tissue, which in turn contributes extensively to neurologic injury. With more recent focus on innate immune processes, it appears that necrotic, but not apoptotic, death mechanisms provoke inflammatory responses likely due to the release or production of endogenous ligands that activate resident immune cells of the central nervous system. These ligands comprise a diverse set of proteins, nucleic acids, and glycosaminoglycans, including heat shock proteins, HMGB1, RNA, DNA, hyaluronan, and heparin sulfate, that stimulate innate immune mechanisms largely through Toll-like receptors (TLRs). The blockade of interactions between endogenous ligands and TLRs may enable neuroprotective therapeutic strategies for a variety of neurologic diseases.

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References

  • Alexopoulou, L., Holt, A. C., Medzhitov, R., & Flavell, R. A. (2001). Recognition of double-stranded RNA and activation of NF-kappaB by Toll-like receptor 3. Nature, 413(6857), 732–738.

    CAS  PubMed  Google Scholar 

  • Andersson, A., Covacu, R., Sunnemark, D., Danilov, A. I., Dal Bianco, A., Khademi, M., et al. (2008). Pivotal advance: HMGB1 expression in active lesions of human and experimental multiple sclerosis. Journal of Leukocyte Biology, 84(5), 1248–1255.

    CAS  PubMed  Google Scholar 

  • Asea, A., Rehli, M., Kabingu, E., Boch, J. A., Bare, O., Auron, P. E., et al. (2002). Novel signal transduction pathway utilized by extracellular HSP70: Role of toll-like receptor (TLR) 2 and TLR4. The Journal of Biological Chemistry, 277(17), 15028–15034.

    CAS  PubMed  Google Scholar 

  • Ausseil, J., Desmaris, N., Bigou, S., Attali, R., Corbineau, S., Vitry, S., et al. (2008). Early neurodegeneration progresses independently of microglial activation by heparan sulfate in the brain of mucopolysaccharidosis IIIB mice. PLoS ONE, 3(5), e2296.

    PubMed  Google Scholar 

  • Baker-LePain, J. C., Sarzotti, M., & Nicchitta, C. V. (2004). Glucose-regulated protein 94/glycoprotein 96 elicits bystander activation of CD4+ T cell Th1 cytokine production in vivo. Journal of Immunology, 172(7), 4195–4203.

    CAS  Google Scholar 

  • Barton, G. M., & Medzhitov, R. (2002). Toll-like receptors and their ligands. Current Topics in Microbiology and Immunology, 270, 81–92.

    CAS  PubMed  Google Scholar 

  • Basu, S., Binder, R. J., Ramalingam, T., & Srivastava, P. K. (2001). CD91 is a common receptor for heat shock proteins gp96, hsp90, hsp70, and calreticulin. Immunity, 14(3), 303–313.

    CAS  PubMed  Google Scholar 

  • Berwin, B., Hart, J. P., Rice, S., Gass, C., Pizzo, S. V., Post, S. R., et al. (2003). Scavenger receptor-A mediates gp96/GRP94 and calreticulin internalization by antigen-presenting cells. EMBO Journal, 22(22), 6127–6136.

    CAS  PubMed  Google Scholar 

  • Bianchi, M. E. (2007). DAMPs, PAMPs and alarmins: All we need to know about danger. Journal of Leukocyte Biology, 81(1), 1–5.

    CAS  PubMed  Google Scholar 

  • Binder, R. J., Han, D. K., & Srivastava, P. K. (2000). CD91: A receptor for heat shock protein gp96. Nature Immunology, 1(2), 151–155.

    CAS  PubMed  Google Scholar 

  • Biragyn, A., Ruffini, P. A., Leifer, C. A., Klyushnenkova, E., Shakhov, A., Chertov, O., et al. (2002). Toll-like receptor 4-dependent activation of dendritic cells by beta-defensin 2. Science, 298(5595), 1025–1029.

    CAS  PubMed  Google Scholar 

  • Boillee, S., Yamanaka, K., Lobsiger, C. S., Copeland, N. G., Jenkins, N. A., Kassiotis, G., et al. (2006). Onset and progression in inherited ALS determined by motor neurons and microglia. Science, 312(5778), 1389–1392.

    CAS  PubMed  Google Scholar 

  • Bowman, C. C., Rasley, A., Tranguch, S. L., & Marriott, I. (2003). Cultured astrocytes express toll-like receptors for bacterial products. Glia, 43(3), 281–291.

    PubMed  Google Scholar 

  • Bsibsi, M., Ravid, R., Gveric, D., & van Noort, J. M. (2002). Broad expression of Toll-like receptors in the human central nervous system. Journal of Neuropathology and Experimental Neurology, 61(11), 1013–1021.

    CAS  PubMed  Google Scholar 

  • Bsibsi, M., Persoon-Deen, C., Verwer, R. W., Meeuwsen, S., Ravid, R., & Van Noort, J. M. (2006). Toll-like receptor 3 on adult human astrocytes triggers production of neuroprotective mediators. Glia, 53(7), 688–695.

    PubMed  Google Scholar 

  • Calderwood, S. K., Mambula, S. S., & Gray, P. J., Jr. (2007). Extracellular heat shock proteins in cell signaling and immunity. Annals of the New York Academy of Sciences, 1113, 28–39.

    CAS  PubMed  Google Scholar 

  • Cameron, J. S., Alexopoulou, L., Sloane, J. A., DiBernardo, A. B., Ma, Y., Kosaras, B., et al. (2007). Toll-like receptor 3 is a potent negative regulator of axonal growth in mammals. Journal of Neuroscience, 27(47), 13033–13041.

    CAS  PubMed  Google Scholar 

  • Cao, C., Yang, Q., Lv, F., Cu, J., Fu, H., & JZ, W. (2007). Reduced cerebral ischemia–reperfusion injury in Toll-like receptor 4 deficient mice. Biochemical and Biophysical Research Communications, 353(2), 509–514.

    CAS  PubMed  Google Scholar 

  • Carpentier, P. A., Begolka, W. S., Olson, J. K., Elhofy, A., Karpus, W. J., & Miller, S. D. (2005). Differential activation of astrocytes by innate and adaptive immune stimuli. Glia, 49(3), 360–374.

    PubMed  Google Scholar 

  • Caso, J. R., Pradillo, J. M., Hurtado, O., Lorenzo, P., Moro, M. A., & Lizasoain, I. (2007). Toll-like receptor 4 is involved in brain damage and inflammation after experimental stroke. Circulation, 115(12), 1599–1608.

    CAS  PubMed  Google Scholar 

  • Caso, J. R., Pradillo, J. M., Hurtado, O., Leza, J. C., Moro, M. A., & Lizasoain, I. (2008). Toll-like receptor 4 is involved in subacute stress-induced neuroinflammation and in the worsening of experimental stroke. Stroke, 39(4), 1314–1320.

    CAS  PubMed  Google Scholar 

  • Chang, G. H., Barbaro, N. M., & Pieper, R. O. (2000). Phosphatidylserine-dependent phagocytosis of apoptotic glioma cells by normal human microglia, astrocytes, and glioma cells. Neuro-oncology, 2(3), 174–183.

    CAS  PubMed  Google Scholar 

  • Chen, K., Iribarren, P., Hu, J., Chen, J., Gong, W., Cho, E., et al. (2006). Activation of Toll-like receptor 2 on microglia promotes cell uptake of Alzheimer disease-associated amyloid beta peptide. The Journal of Biological Chemistry, 281(6), 3651–3659.

    CAS  PubMed  Google Scholar 

  • Clark, A., D’Aquisto, F., Gentry, C., Marchand, F., McMahon, S., & Malcangio, M. (2006). Rapid co-release of interleukin 1beta and caspase 1 in spinal cord inflammation. Journal of Neurochemistry, 99(3), 868–880.

    CAS  PubMed  Google Scholar 

  • Clayton, A., Turkes, A., Navabi, H., Mason, M. D., & Tabi, Z. (2005). Induction of heat shock proteins in B-cell exosomes. Journal of Cell Science, 118(Pt 16), 3631–3638.

    CAS  PubMed  Google Scholar 

  • Covacu, R., Arvidsson, L., Andersson, A., Khademi, M., Erlandsson-Harris, H., Harris, R., et al. (2009). TLR activation induces TNF-alpha production from adult neural stem/progenitor cells. Journal of Immunology, 182(11), 6889–6895.

    CAS  Google Scholar 

  • Curtin, J. F., Liu, N., Candolfi, M., Xiong, W., Assi, H., Yagiz, K., et al. (2009). HMGB1 mediates endogenous TLR2 activation and brain tumor regression. PLoS Medicine, 6(1), e10.

    PubMed  Google Scholar 

  • Diebold, S. S., Kaisho, T., Hemmi, H., Akira, S., & Reis e Sousa, C. (2004). Innate antiviral responses by means of TLR7-mediated recognition of single-stranded RNA. Science, 303(5663), 1529–1531.

    CAS  PubMed  Google Scholar 

  • Ehrentraut, S., Frede, S., Stapel, H., Mengden, T., Grohé, C., Fandrey, J., et al. (2007). Antagonism of lipopolysaccharide-induced blood pressure attenuation and vascular contractility. Arteriosclerosis, Thrombosis, and Vascular Biology, 27(10), 2170–2176.

    CAS  PubMed  Google Scholar 

  • El Chamy, L., Leclerc, V., Caldelari, I., & Reichhart, J. M. (2008). Sensing of ‘danger signals’ and pathogen-associated molecular patterns defines binary signaling pathways ‘upstream’ of Toll. Nature Immunology, 9(10), 1165–1170.

    CAS  PubMed  Google Scholar 

  • Farina, C., Aloisi, F., & Meinl, E. (2007). Astrocytes are active players in cerebral innate immunity. Trends in Immunology, 28(3), 138–145.

    CAS  PubMed  Google Scholar 

  • Floto, R. A., MacAry, P. A., Boname, J. M., Mien, T. S., Kampmann, B., Hair, J. R., et al. (2006). Dendritic cell stimulation by mycobacterial Hsp70 is mediated through CCR5. Science, 314(5798), 454–458.

    CAS  PubMed  Google Scholar 

  • Gallucci, S., Lolkema, M., & Matzinger, P. (1999). Natural adjuvants: Endogenous activators of dendritic cells. Nature Medicine, 5(11), 1249–1255.

    CAS  PubMed  Google Scholar 

  • Gao, B., & Tsan, M. F. (2003). Recombinant human heat shock protein 60 does not induce the release of tumor necrosis factor alpha from murine macrophages. The Journal of Biological Chemistry, 278(25), 22523–22529.

    CAS  PubMed  Google Scholar 

  • Gao, B., Wang, Y., & Tsan, M. (2006). The heat sensitivity of cytokine-inducing effect of lipopolysaccharide. Journal of Leukocyte Biology, 80(2), 359–366.

    CAS  PubMed  Google Scholar 

  • Gitlin, L., Barchet, W., Gilfillan, S., Cella, M., Beutler, B., Flavell, R. A., et al. (2006). Essential role of mda-5 in type I IFN responses to polyriboinosinic:polyribocytidylic acid and encephalomyocarditis picornavirus. Proceedings of the National Academy of Sciences of the United States of America, 103(22), 8459–8464.

    CAS  PubMed  Google Scholar 

  • Giunta, B., Fernandez, F., Nikolic, W. V., Obregon, D., Rrapo, E., Town, T., et al. (2008). Inflammaging as a prodrome to Alzheimer’s disease. Journal of Neuroinflammation, 5, 51.

    PubMed  Google Scholar 

  • Golstein, P., & Kroemer, G. (2007). Cell death by necrosis: Towards a molecular definition. Trends in Biochemical Sciences, 32(1), 37–43.

    CAS  PubMed  Google Scholar 

  • Hayashi, F., Smith, K. D., Ozinsky, A., Hawn, T. R., Yi, E. C., Goodlett, D. R., et al. (2001). The innate immune response to bacterial flagellin is mediated by Toll-like receptor 5. Nature, 410(6832), 1099–1103.

    CAS  PubMed  Google Scholar 

  • Heil, F., Hemmi, H., Hochrein, H., Ampenberger, F., Kirschning, C., Akira, S., et al. (2004). Species-specific recognition of single-stranded RNA via toll-like receptor 7 and 8. Science, 303(5663), 1526–1529.

    CAS  PubMed  Google Scholar 

  • Hemmi, H., Takeuchi, O., Kawai, T., Kaisho, T., Sato, S., Sanjo, H., et al. (2000). A Toll-like receptor recognizes bacterial DNA. Nature, 408(6813), 740–745.

    CAS  PubMed  Google Scholar 

  • Hertz, C. J., Wu, Q., Porter, E. M., Zhang, Y. J., Weismuller, K. H., Godowski, P. J., et al. (2003). Activation of Toll-like receptor 2 on human tracheobronchial epithelial cells induces the antimicrobial peptide human beta defensin-2. Journal of Immunology, 171(12), 6820–6826.

    CAS  Google Scholar 

  • Hirschfeld, M., Kirschning, C. J., Schwandner, R., Wesche, H., Weis, J. H., Wooten, R. M., et al. (1999). Cutting edge: Inflammatory signaling by Borrelia burgdorferi lipoproteins is mediated by toll-like receptor 2. Journal of Immunology, 163(5), 2382–2386.

    CAS  Google Scholar 

  • Hua, F., Ma, J., Ha, T., Kelley, J. L., Kao, R. L., Schweitzer, J. B., et al. (2009). Differential roles of TLR2 and TLR4 in acute focal cerebral ischemia/reperfusion injury in mice. Brain Research, 1262, 100–108.

    CAS  PubMed  Google Scholar 

  • Hussain, S. F., Yang, D., Suki, D., Grimm, E., & Heimberger, A. B. (2006). Innate immune functions of microglia isolated from human glioma patients. Journal of Translational Medicine, 4, 15.

    PubMed  Google Scholar 

  • Jack, C. S., Arbour, N., Manusow, J., Montgrain, V., Blain, M., McCrea, E., et al. (2005). TLR signaling tailors innate immune responses in human microglia and astrocytes. Journal of Immunology, 175(7), 4320–4330.

    CAS  Google Scholar 

  • Jana, M., Palencia, C., & Pahan, K. (2008). Fibrillar amyloid-beta peptides activate microglia via TLR2: Implications for Alzheimer’s disease. Journal of Immunology, 181(10), 7254–7262.

    CAS  Google Scholar 

  • Jiang, D., Liang, J., Fan, J., Yu, S., Chen, S., Luo, Y., et al. (2005). Regulation of lung injury and repair by Toll-like receptors and hyaluronan. Nature Medicine, 11(11), 1173–1179.

    CAS  PubMed  Google Scholar 

  • Jin, M., Kim, S., Heo, J., Lee, M., Kim, H., Paik, S., et al. (2007). Crystal structure of the TLR1-TLR2 heterodimer induced by binding of a tri-acylated lipopeptide. Cell, 130(6), 1071–1082.

    CAS  PubMed  Google Scholar 

  • Johnson, G. B., Brunn, G. J., Kodaira, Y., & Platt, J. L. (2002). Receptor-mediated monitoring of tissue well-being via detection of soluble heparan sulfate by Toll-like receptor 4. Journal of Immunology, 168(10), 5233–5239.

    CAS  Google Scholar 

  • Kakimura, J., Kitamura, Y., Takata, K., Umeki, M., Suzuki, S., Shibagaki, K., et al. (2002). Microglial activation and amyloid-beta clearance induced by exogenous heat-shock proteins. FASEB Journal, 16(6), 601–603.

    CAS  PubMed  Google Scholar 

  • Kang, J., & Rivest, S. (2007). MyD88-deficient bone marrow cells accelerate onset and reduce survival in a mouse model of amyotrophic lateral sclerosis. Journal of Cell Biology, 179(6), 1219–1230.

    CAS  PubMed  Google Scholar 

  • Kariko, K., Ni, H., Capodici, J., Lamphier, M., & Weissman, D. (2004). mRNA is an endogenous ligand for Toll-like receptor 3. The Journal of Biological Chemistry, 279(13), 12542–12550.

    CAS  PubMed  Google Scholar 

  • Kigerl, K. A., Lai, W., Rivest, S., Hart, R. P., Satoskar, A. R., & Popovich, P. G. (2007). Toll-like receptor (TLR)-2 and TLR-4 regulate inflammation, gliosis, and myelin sparing after spinal cord injury. Journal of Neurochemistry, 102(1), 37–50.

    CAS  PubMed  Google Scholar 

  • Kilic, U., Kilic, E., Matter, C. M., Bassetti, C. L., & Hermann, D. M. (2008). TLR-4 deficiency protects against focal cerebral ischemia and axotomy-induced neurodegeneration. Neurobiology of Diseases, 31(1), 33–40.

    CAS  Google Scholar 

  • Kim, J. B., Sig Choi, J., Yu, Y. M., Nam, K., Piao, C. S., Kim, S. W., et al. (2006). HMGB1, a novel cytokine-like mediator linking acute neuronal death and delayed neuroinflammation in the postischemic brain. Journal of Neuroscience, 26(24), 6413–6421.

    CAS  PubMed  Google Scholar 

  • Kim, D., Kim, M. A., Cho, I. H., Kim, M. S., Lee, S., Jo, E. K., et al. (2007). A critical role of toll-like receptor 2 in nerve injury-induced spinal cord glial cell activation and pain hypersensitivity. The Journal of Biological Chemistry, 282(20), 14975–14983.

    CAS  PubMed  Google Scholar 

  • Kodaira, Y., Nair, S. K., Wrenshall, L. E., Gilboa, E., & Platt, J. L. (2000). Phenotypic and functional maturation of dendritic cells mediated by heparan sulfate. Journal of Immunology, 165(3), 1599–1604.

    CAS  Google Scholar 

  • Lathia, J. D., Okun, E., Tang, S. C., Griffioen, K., Cheng, A., Mughal, M. R., et al. (2008). Toll-like receptor 3 is a negative regulator of embryonic neural progenitor cell proliferation. Journal of Neuroscience, 28(51), 13978–13984.

    CAS  PubMed  Google Scholar 

  • Ledeboer, A., Brevé, J., Wierinckx, A., van der Jagt, S., Bristow, A., Leysen, J., et al. (2002). Expression and regulation of interleukin-10 and interleukin-10 receptor in rat astroglial and microglial cells. European Journal of Neuroscience, 16(7), 1175–1185.

    PubMed  Google Scholar 

  • Lee, J., Chuang, T. H., Redecke, V., She, L., Pitha, P. M., Carson, D. A., et al. (2003). Molecular basis for the immunostimulatory activity of guanine nucleoside analogs: Activation of Toll-like receptor 7. Proceedings of the National Academy of Sciences of the United States of America, 100(11), 6646–6651.

    CAS  PubMed  Google Scholar 

  • Lehnardt, S., Lachance, C., Patrizi, S., Lefebvre, S., Follett, P. L., Jensen, F. E., et al. (2002). The toll-like receptor TLR4 is necessary for lipopolysaccharide-induced oligodendrocyte injury in the CNS. Journal of Neuroscience, 22(7), 2478–2486.

    CAS  PubMed  Google Scholar 

  • Lehnardt, S., Massillon, L., Follett, P., Jensen, F. E., Ratan, R., Rosenberg, P. A., et al. (2003). Activation of innate immunity in the CNS triggers neurodegeneration through a Toll-like receptor 4-dependent pathway. Proceedings of the National Academy of Sciences of the United States of America, 100(14), 8514–8519.

    CAS  PubMed  Google Scholar 

  • Lehnardt, S., Henneke, P., Lien, E., Kasper, D. L., Volpe, J. J., Bechmann, I., et al. (2006). A mechanism for neurodegeneration induced by group B streptococci through activation of the TLR2/MyD88 pathway in microglia. Journal of Immunology, 177(1), 583–592.

    CAS  Google Scholar 

  • Lehnardt, S., Lehmann, S., Kaul, D., Tschimmel, K., Hoffmann, O., Cho, S., et al. (2007). Toll-like receptor 2 mediates CNS injury in focal cerebral ischemia. Journal of Neuroimmunology, 190(1–2), 28–33.

    CAS  PubMed  Google Scholar 

  • Lehnardt, S., Schott, E., Trimbuch, T., Laubisch, D., Krueger, C., Wulczyn, G., et al. (2008). A vicious cycle involving release of heat shock protein 60 from injured cells and activation of toll-like receptor 4 mediates neurodegeneration in the CNS. Journal of Neuroscience, 28(10), 2320–2331.

    CAS  PubMed  Google Scholar 

  • Leonard, J., Ghirlando, R., Askins, J., Bell, J., Margulies, D., Davies, D., et al. (2008). The TLR3 signaling complex forms by cooperative receptor dimerization. Proceedings of the National Academy of Sciences of the United States of America, 105(1), 258–263.

    CAS  PubMed  Google Scholar 

  • Li, M., Carpio, D. F., Zheng, Y., Bruzzo, P., Singh, V., Ouaaz, F., et al. (2001). An essential role of the NF-kappa B/Toll-like receptor pathway in induction of inflammatory and tissue-repair gene expression by necrotic cells. Journal of Immunology, 166(12), 7128–7135.

    CAS  Google Scholar 

  • Lien, E., Sellati, T. J., Yoshimura, A., Flo, T. H., Rawadi, G., Finberg, R. W., et al. (1999). Toll-like receptor 2 functions as a pattern recognition receptor for diverse bacterial products. The Journal of Biological Chemistry, 274(47), 33419–33425.

    CAS  PubMed  Google Scholar 

  • Liu, B., Dai, J., Zheng, H., Stoilova, D., Sun, S., & Li, Z. (2003). Cell surface expression of an endoplasmic reticulum resident heat shock protein gp96 triggers MyD88-dependent systemic autoimmune diseases. Proceedings of the National Academy of Sciences of the United States of America, 100(26), 15824–15829.

    CAS  PubMed  Google Scholar 

  • Liu, S., Stolz, D. B., Sappington, P. L., Macias, C. A., Killeen, M. E., Tenhunen, J. J., et al. (2006). HMGB1 is secreted by immunostimulated enterocytes and contributes to cytomix-induced hyperpermeability of Caco-2 monolayers. American Journal of Physiology. Cell Physiology, 290(4), C990–C999.

    CAS  PubMed  Google Scholar 

  • Liu, L., Botos, I., Wang, Y., Leonard, J., Shiloach, J., Segal, D., et al. (2008). Structural basis of toll-like receptor 3 signaling with double-stranded RNA. Science, 320(5874), 379–381.

    CAS  PubMed  Google Scholar 

  • Liu-Bryan, R., Scott, P., Sydlaske, A., Rose, D. M., & 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 and Rheumatism, 52(9), 2936–2946.

    CAS  PubMed  Google Scholar 

  • Ma, Y., Li, J., Chiu, I., Wang, Y., Sloane, J. A., Lu, J., et al. (2006). Toll-like receptor 8 functions as a negative regulator of neurite outgrowth and inducer of neuronal apoptosis. Journal of Cell Biology, 175(2), 209–215.

    CAS  PubMed  Google Scholar 

  • Mambula, S. S., & Calderwood, S. K. (2006). Heat shock protein 70 is secreted from tumor cells by a nonclassical pathway involving lysosomal endosomes. Journal of Immunology, 177(11), 7849–7857.

    CAS  Google Scholar 

  • Martinon, F., Petrilli, V., Mayor, A., Tardivel, A., & Tschopp, J. (2006). Gout-associated uric acid crystals activate the NALP3 inflammasome. Nature, 440(7081), 237–241.

    CAS  PubMed  Google Scholar 

  • Means, T. K., Golenbock, D. T., & Fenton, M. J. (2000). Structure and function of Toll-like receptor proteins. Life Science, 68(3), 241–258.

    CAS  Google Scholar 

  • Means, T. K., Latz, E., Hayashi, F., Murali, M. R., Golenbock, D. T., & Luster, A. D. (2005). Human lupus autoantibody-DNA complexes activate DCs through cooperation of CD32 and TLR9. Journal of Clinical Investigation, 115(2), 407–417.

    CAS  PubMed  Google Scholar 

  • Mizuno, T., Sawada, M., Marunouchi, T., & Suzumura, A. (1994). Production of interleukin-10 by mouse glial cells in culture. Biochemical and Biophysical Research Communications, 205(3), 1907–1915.

    CAS  PubMed  Google Scholar 

  • Morisato, D., & Anderson, K. V. (1994). The spatzle gene encodes a component of the extracellular signaling pathway establishing the dorsal–ventral pattern of the Drosophila embryo. Cell, 76(4), 677–688.

    CAS  PubMed  Google Scholar 

  • Morrison, D., & Jacobs, D. (1976a). Binding of polymyxin B to the lipid A portion of bacterial lipopolysaccharides. Immunochemistry, 13, 813–818.

    CAS  PubMed  Google Scholar 

  • Morrison, D., & Jacobs, D. (1976b). Inhibition of lipopolysaccharide-initiated activation of serum complement by polymyxin B. Infection and Immunity, 13, 298–301.

    CAS  PubMed  Google Scholar 

  • Negishi, H., Osawa, T., Ogami, K., Ouyang, X., Sakaguchi, S., Koshiba, R., et al. (2008). A critical link between Toll-like receptor 3 and type II interferon signaling pathways in antiviral innate immunity. Proceedings of the National Academy of Sciences of the United States of America, 105(51), 20446–204451.

    CAS  PubMed  Google Scholar 

  • Nitatori, T., Sato, N., Waguri, S., Karasawa, Y., Araki, H., Shibanai, K., et al. (1995). Delayed neuronal death in the CA1 pyramidal cell layer of the gerbil hippocampus following transient ischemia is apoptosis. Journal of Neuroscience, 15(2), 1001–1011.

    CAS  PubMed  Google Scholar 

  • Ohashi, K., Burkart, V., Flohe, S., & Kolb, H. (2000). Heat shock protein 60 is a putative endogenous ligand of the toll-like receptor-4 complex. Journal of Immunology, 164(2), 558–561.

    CAS  Google Scholar 

  • Okamura, Y., Watari, M., Jerud, E. S., Young, D. W., Ishizaka, S. T., Rose, J., et al. (2001). The extra domain A of fibronectin activates Toll-like receptor 4. The Journal of Biological Chemistry, 276(13), 10229–10233.

    CAS  PubMed  Google Scholar 

  • Olson, J. K., & Miller, S. D. (2004). Microglia initiate central nervous system innate and adaptive immune responses through multiple TLRs. Journal of Immunology, 173(6), 3916–3924.

    CAS  Google Scholar 

  • Park, J. S., Svetkauskaite, D., He, Q., Kim, J. Y., Strassheim, D., Ishizaka, A., et al. (2004). Involvement of toll-like receptors 2 and 4 in cellular activation by high mobility group box 1 protein. The Journal of Biological Chemistry, 279(9), 7370–7377.

    CAS  PubMed  Google Scholar 

  • Park, J. S., Gamboni-Robertson, F., He, Q., Svetkauskaite, D., Kim, J. Y., Strassheim, D., et al. (2006). High mobility group box 1 protein interacts with multiple Toll-like receptors. American Journal of Physiology. Cell Physiology, 290(3), C917–C924.

    CAS  PubMed  Google Scholar 

  • Park, B., Song, D., Kim, H., Choi, B., Lee, H., & Lee, J. (2009). The structural basis of lipopolysaccharide recognition by the TLR4-MD-2 complex. Nature, 458(7242), 1191–1195.

    CAS  PubMed  Google Scholar 

  • Petersen, B., Bloch, K., Ichinose, F., Shin, H., Shigematsu, M., Bagchi, A., et al. (2008). Activation of Toll-like receptor 2 impairs hypoxic pulmonary vasoconstriction in mice. American Journal of Physiology Lung Cellular and Molecular Physiology, 294(2), 300–308.

    Google Scholar 

  • Pineau, I., & Lacroix, S. (2007). Proinflammatory cytokine synthesis in the injured mouse spinal cord: Multiphasic expression pattern and identification of the cell types involved. Journal of Comparative Neurology, 500(2), 267–285.

    CAS  PubMed  Google Scholar 

  • Piotrowicz, B., & McCartney, A. (1986). Effect of heat on endotoxin in plasma and in pyrogen-free water, as measured in the Limulus amoebocyte lysate assay. Canadian Journal of Microbiology, 32, 763–764.

    Article  CAS  PubMed  Google Scholar 

  • Popovic, K., Ek, M., Espinosa, A., Padyukov, L., Harris, H. E., Wahren-Herlenius, M., et al. (2005). Increased expression of the novel proinflammatory cytokine high mobility group box chromosomal protein 1 in skin lesions of patients with lupus erythematosus. Arthritis and Rheumatism, 52(11), 3639–3645.

    CAS  PubMed  Google Scholar 

  • Porto, A., Palumbo, R., Pieroni, M., Aprigliano, G., Chiesa, R., Sanvito, F., et al. (2006). Smooth muscle cells in human atherosclerotic plaques secrete and proliferate in response to high mobility group box 1 protein. FASEB Journal, 20(14), 2565–2566.

    CAS  PubMed  Google Scholar 

  • Reed, R. C., Berwin, B., Baker, J. P., & Nicchitta, C. V. (2003). GRP94/gp96 elicits ERK activation in murine macrophages. A role for endotoxin contamination in NF-kappa B activation and nitric oxide production. The Journal of Biological Chemistry, 34, 31853–31860.

    Google Scholar 

  • Richard, K., Filali, M., Préfontaine, P., & Rivest, S. (2008). Toll-like receptor 2 acts as a natural innate immune receptor to clear amyloid beta 1–42 and delay the cognitive decline in a mouse model of Alzheimer’s disease. Journal of Neuroscience, 28(22), 5784–5793.

    CAS  PubMed  Google Scholar 

  • Roelofs, M. F., Boelens, W. C., Joosten, L. A., Abdollahi-Roodsaz, S., Geurts, J., Wunderink, L. U., et al. (2006). Identification of small heat shock protein B8 (HSP22) as a novel TLR4 ligand and potential involvement in the pathogenesis of rheumatoid arthritis. Journal of Immunology, 176(11), 7021–7027.

    CAS  Google Scholar 

  • Rolls, A., Shechter, R., London, A., Ziv, Y., Ronen, A., Levy, R., et al. (2007). Toll-like receptors modulate adult hippocampal neurogenesis. Nature Cell Biology, 9(9), 1081–1088.

    CAS  PubMed  Google Scholar 

  • Rose, D., & Chiba, A. (1999). A single growth cone is capable of integrating simultaneously presented and functionally distinct molecular cues during target recognition. Journal of Neuroscience, 19(12), 4899–4906.

    CAS  PubMed  Google Scholar 

  • Roth, S. (1994). Axis determination. Proteolytic generation of a morphogen. Curr Biol, 4(8), 755–777.

    CAS  PubMed  Google Scholar 

  • Sauter, B., Albert, M. L., Francisco, L., Larsson, M., Somersan, S., & Bhardwaj, N. (2000). Consequences of cell death: Exposure to necrotic tumor cells, but not primary tissue cells or apoptotic cells, induces the maturation of immunostimulatory dendritic cells. Journal of Experimental Medicine, 191(3), 423–434.

    CAS  PubMed  Google Scholar 

  • Scaffidi, P., Misteli, T., & Bianchi, M. E. (2002). Release of chromatin protein HMGB1 by necrotic cells triggers inflammation. Nature, 418(6894), 191–195.

    CAS  PubMed  Google Scholar 

  • Scheibner, K. A., Lutz, M. A., Boodoo, S., Fenton, M. J., Powell, J. D., & Horton, M. R. (2006). Hyaluronan fragments act as an endogenous danger signal by engaging TLR2. Journal of Immunology, 177(2), 1272–1281.

    CAS  Google Scholar 

  • Schneider, D. S., Jin, Y., Morisato, D., & Anderson, K. V. (1994). A processed form of the Spatzle protein defines dorsal–ventral polarity in the Drosophila embryo. Development, 120(5), 1243–1250.

    CAS  PubMed  Google Scholar 

  • Schwandner, R., Dziarski, R., Wesche, H., Rothe, M., & Kirschning, C. J. (1999). Peptidoglycan- and lipoteichoic acid-induced cell activation is mediated by toll-like receptor 2. The Journal of Biological Chemistry, 274(25), 17406–17409.

    CAS  PubMed  Google Scholar 

  • Shi, Y., Evans, J. E., & Rock, K. L. (2003). Molecular identification of a danger signal that alerts the immune system to dying cells. Nature, 425(6957), 516–521.

    CAS  PubMed  Google Scholar 

  • Shin, H., Lee, H., Park, J., Hyun, H., Sohn, H., Lee, D., et al. (2007). Kinetics of binding of LPS to recombinant CD14, TLR4, and MD-2 proteins. Molecules and Cells, 24(1), 119–124.

    CAS  PubMed  Google Scholar 

  • Sonnenfeld, M. J., & Jacobs, J. R. (1995). Macrophages and glia participate in the removal of apoptotic neurons from the Drosophila embryonic nervous system. Journal of Comparative Neurology, 359(4), 644–652.

    CAS  PubMed  Google Scholar 

  • Spinner, D. S., Cho, I. S., Park, S. Y., Kim, J. I., Meeker, H. C., Ye, X., et al. (2008). Accelerated prion disease pathogenesis in Toll-like receptor 4 signaling-mutant mice. Journal of Virology, 82(21), 10701–10708.

    CAS  PubMed  Google Scholar 

  • Syntichaki, P., & Tavernarakis, N. (2003). The biochemistry of neuronal necrosis: Rogue biology? Nature Reviews. Neuroscience, 4(8), 672–684.

    CAS  PubMed  Google Scholar 

  • Taguchi, A., Blood, D. C., del Toro, G., Canet, A., Lee, D. C., Qu, W., et al. (2000). Blockade of RAGE-amphoterin signalling suppresses tumour growth and metastases. Nature, 405(6784), 354–560.

    CAS  PubMed  Google Scholar 

  • Takeda, K., & Akira, S. (2005). Toll-like receptors in innate immunity. International Immunology, 17(1), 1–14.

    CAS  PubMed  Google Scholar 

  • Tang, S. C., Arumugam, T. V., Xu, X., Cheng, A., Mughal, M. R., Jo, D. G., et al. (2007). Pivotal role for neuronal Toll-like receptors in ischemic brain injury and functional deficits. Proceedings of the National Academy of Sciences of the United States of America, 104(34), 13798–13803.

    CAS  PubMed  Google Scholar 

  • Tang, S. C., Lathia, J. D., Selvaraj, P. K., Jo, D. G., Mughal, M. R., Cheng, A., et al. (2008). Toll-like receptor-4 mediates neuronal apoptosis induced by amyloid beta-peptide and the membrane lipid peroxidation product 4-hydroxynonenal. Experimental Neurology, 213(1), 114–121.

    CAS  PubMed  Google Scholar 

  • Termeer, C., Benedix, F., Sleeman, J., Fieber, C., Voith, U., Ahrens, T., et al. (2002). Oligosaccharides of Hyaluronan activate dendritic cells via toll-like receptor 4. Journal of Experimental Medicine, 195(1), 99–111.

    CAS  PubMed  Google Scholar 

  • Theriault, J. R., Mambula, S. S., Sawamura, T., Stevenson, M. A., & Calderwood, S. K. (2005). Extracellular HSP70 binding to surface receptors present on antigen presenting cells and endothelial/epithelial cells. FEBS Letters, 579(9), 1951–1960.

    CAS  PubMed  Google Scholar 

  • Town, T., Jeng, D., Alexopoulou, L., Tan, J., & Flavell, R. A. (2006). Microglia recognize double-stranded RNA via TLR3. Journal of Immunology, 176(6), 3804–3812.

    CAS  Google Scholar 

  • Tsung, A., Klune, J. R., Zhang, X., Jeyabalan, G., Cao, Z., Peng, X., et al. (2007). HMGB1 release induced by liver ischemia involves Toll-like receptor 4 dependent reactive oxygen species production and calcium-mediated signaling. Journal of Experimental Medicine, 204(12), 2913–2923.

    CAS  PubMed  Google Scholar 

  • Udan, M., Ajit, D., Crouse, N., & Nichols, M. (2007). Toll-like receptors 2 and 4 mediate Abeta(1–42) activation of the innate immune response in a human monocytic cell line. Journal of Neurochemistry, 104(2), 524–533.

    PubMed  Google Scholar 

  • Urbonaviciute, V., Furnrohr, B. G., Meister, S., Munoz, L., Heyder, P., De Marchis, F., et al. (2008). Induction of inflammatory and immune responses by HMGB1-nucleosome complexes: Implications for the pathogenesis of SLE. Journal of Experimental Medicine, 205(13), 3007–3018.

    CAS  PubMed  Google Scholar 

  • Vabulas, R. M., Ahmad-Nejad, P., da Costa, C., Miethke, T., Kirschning, C. J., Hacker, H., et al. (2001). Endocytosed HSP60s use toll-like receptor 2 (TLR2) and TLR4 to activate the toll/interleukin-1 receptor signaling pathway in innate immune cells. The Journal of Biological Chemistry, 276(33), 31332–31339.

    CAS  PubMed  Google Scholar 

  • Vabulas, R. M., Ahmad-Nejad, P., Ghose, S., Kirschning, C. J., Issels, R. D., & Wagner, H. (2002a). HSP70 as endogenous stimulus of the Toll/interleukin-1 receptor signal pathway. The Journal of Biological Chemistry, 277(17), 15107–15112.

    CAS  PubMed  Google Scholar 

  • Vabulas, R. M., Braedel, S., Hilf, N., Singh-Jasuja, H., Herter, S., Ahmad-Nejad, P., et al. (2002b). The endoplasmic reticulum-resident heat shock protein Gp96 activates dendritic cells via the Toll-like receptor 2/4 pathway. The Journal of Biological Chemistry, 277(23), 20847–20853.

    CAS  PubMed  Google Scholar 

  • Vikström, E. (2002). The immunosuppressive activity of chemically modified lipopolysaccharide of Shigella sonnei. Immunology Letters, 80(1), 15–19.

    PubMed  Google Scholar 

  • Wang, Y., Kelly, C. G., Karttunen, J. T., Whittall, T., Lehner, P. J., Duncan, L., et al. (2001). CD40 is a cellular receptor mediating mycobacterial heat shock protein 70 stimulation of CC-chemokines. Immunity, 15(6), 971–983.

    CAS  PubMed  Google Scholar 

  • Yang, D., Chen, Q., Su, S. B., Zhang, P., Kurosaka, K., Caspi, R. R., et al. (2008). Eosinophil-derived neurotoxin acts as an alarmin to activate the TLR2-MyD88 signal pathway in dendritic cells and enhances Th2 immune responses. Journal of Experimental Medicine, 205(1), 79–90.

    CAS  PubMed  Google Scholar 

  • Yarovinsky, F., Zhang, D., Andersen, J. F., Bannenberg, G. L., Serhan, C. N., Hayden, M. S., et al. (2005). TLR11 activation of dendritic cells by a protozoan profilin-like protein. Science, 308(5728), 1626–1629.

    CAS  PubMed  Google Scholar 

  • Yoshiyama, Y., Higuchi, M., Zhang, B., Huang, S. M., Iwata, N., Saido, T. C., et al. (2007). Synapse loss and microglial activation precede tangles in a P301S tauopathy mouse model. Neuron, 53(3), 337–351.

    CAS  PubMed  Google Scholar 

  • Zhang, W., Wang, T., Pei, Z., Miller, D. S., Wu, X., Block, M. L., et al. (2005). Aggregated alpha-synuclein activates microglia: A process leading to disease progression in Parkinson’s disease. FASEB Journal, 19(6), 533–542.

    CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Neurology, Beth Israel Deaconess Medical Center, Center for Life Sciences, Rm. 628, 330 Brookline Ave, Boston, MA, 02215, USA

    Jacob A. Sloane, Daina Blitz & Zachary Margolin

  2. Department of Neurology/Neuroscience, Weill Cornell Medical College, Suite E607, 1300 York Ave, New York, NY, 10021, USA

    Daina Blitz, Zachary Margolin & Timothy Vartanian

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  1. Jacob A. Sloane
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Correspondence to Jacob A. Sloane.

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Sloane, J.A., Blitz, D., Margolin, Z. et al. A Clear and Present Danger: Endogenous Ligands of Toll-like Receptors. Neuromol Med 12, 149–163 (2010). https://doi.org/10.1007/s12017-009-8094-x

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