Abstract
Mammalian Toll-like receptors (TLRs) were first identified in 1997 based on their homology with Drosophila Toll, which mediates innate immunity in the fly. Over the past eight years, the number of manuscripts describing TLR expression and function in the central nervous system (CNS) has been increasing steadily and expanding beyond their traditional roles in infectious diseases to neurodegenerative disorders and injury. Interest in the field serves as the impetus for this volume in the Current Topics in Microbiology and Immunology series entitled Toll-Like Receptors: Roles in Infection and Neuropathology. The first five chapters highlight more traditional roles for TLRs in infectious diseases of the CNS. The second half of the volume discusses recently emerging roles for TLRs in noninfectious neurodegenerative diseases and the challenges faced by these models in identifying endogenous ligands. Several conceptual theories are introduced in various chapters that deal with the dual nature of TLR engagement and whether these signals favor neuroprotective versus neurodegenerative outcomes.
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Abbreviations
- APC:
-
Antigen-presenting cell
- CNS:
-
Central nervous system
- CTMI :
-
Current Topics in Microbiology and Immunology
- DAMP:
-
Danger-associated molecular pattern
- dsRNA:
-
Double-stranded RNA
- FACS:
-
Fluorescent-activated cell sorting
- IFN:
-
Interferon
- IκB:
-
Inhibitory kappa B
- IκK:
-
Inhibitory-κB kinase
- IL:
-
Interleukin
- IL-1R:
-
Interleukin-1 receptor
- IL-18R:
-
Interleukin-18 receptor
- IRAK:
-
Interleukin-1 receptor-associated kinase
- LPS:
-
Lipopolysaccharide
- LTA:
-
Lipoteichoic acid
- MAPK:
-
Mitogen-activated protein kinase
- MyD88:
-
Myeloid differentiation primary-response protein 88
- NF-κB:
-
Nuclear factor kappa B
- NIKNF-κB:
-
inducing kinase
- ODN:
-
Oligodeoxynucleotide
- Pam3Cys:
-
Tripalmitoyl-S-glyceryl-cysteine
- PAMP:
-
Pathogen-associated molecular pattern
- PGN:
-
Peptidoglycan
- Poly I:C:
-
Polyinosine:cytosine
- PRR:
-
Pattern recognition receptor
- ssRNA:
-
Single-stranded RNA
- TIRAP:
-
Toll-interleukin 1 receptor (TIR) domain-containing adaptor protein
- TLR:
-
Toll-like receptor
- TRAF:
-
Tumor necrosis factor receptor-associated factor
- TRIF:
-
TIR-domain-containing adaptor inducing interferon-β
References
Akira S (2006) TLR signaling. Curr Top Microbiol Immunol 311:1–16
Akira S, Takeda K (2004) Toll-like receptor signalling. Nat Rev Immunol 4:499–511
Akira S, Uematsu S, Takeuchi O (2006) Pathogen recognition and innate immunity. Cell 124:783–801
Alexopoulou L, Holt AC, Medzhitov R, Flavell RA (2001) Recognition of double-stranded RNA and activation of NF-kappaB by Toll-like receptor 3. Nature 413:732–738
Anderson KV (2000) Toll signaling pathways in the innate immune response. Curr Opin Immunol 12:13–19
Becher B, Fedorowicz V, Antel JP (1996) Regulation of CD14 expression on human adult central nervous system-derived microglia. J Neurosci Res 45:375–381
Boonstra A, Asselin-Paturel C, Gilliet M, Crain C, Trinchieri G, Liu YJ, O’Garra A (2003) Flexibility of mouse classical and plasmacytoid-derived dendritic cells in directing T helper type 1 and 2 cell development: dependency on antigen dose and differential toll-like receptor ligation. J Exp Med 197:101–109
Bowman CC, Rasley A, Tranguch SL, Marriott I (2003) Cultured astrocytes express toll-like receptors for bacterial products. Glia 43:281–291
Bsibsi M, Ravid R, Gveric D, van Noort JM (2002) Broad expression of Toll-like receptors in the human central nervous system. J Neuropathol Exp Neurol 61(11):1013–1021
Carpentier PA, Begolka WS, Olson JK, Elhofy A, Karpus WJ, Miller SD (2005) Differential activation of astrocytes by innate and adaptive immune stimuli. Glia 49:360–374
Chakravarty S, Herkenham M (2005) Toll-like receptor 4 on nonhematopoietic cells sustains CNS inflammation during endotoxemia, independent of systemic cytokines. J Neurosci 25:1788–1796
Cleveland MG, Gorham JD, Murphy TL, Tuomanen E, Murphy KM (1996) Lipoteichoic acid preparations of gram-positive bacteria induce interleukin-12 through a CD14-dependent pathway. Infect Immun 64:1906–1912
Dalpke AH, Schafer MK, Frey M, Zimmermann S, Tebbe J, Weihe E, Heeg K (2002) Immunostimulatory CpG-DNA activates murine microglia. J Immunol 168:4854–4863
Dobrovolskaia MA, Vogel SN (2002) Toll receptors, CD14, and macrophage activation and deactivation by LPS. Microbes Infect 4:903–914
Dziarski R, Ulmer AJ, Gupta D (2000) Interactions of CD14 with components of gram-positive bacteria. Chem Immunol 74:83–107
Esen N, Kielian T (2005) Recognition of Staphylococcus aureus-derived peptidoglycan (PGN) but not intact bacteria is mediated by CD14 in microglia. J Neuroimmunol 170:93–104
Esen N, Tanga FY, DeLeo JA, Kielian T (2004) Toll-like receptor 2 (TLR2) mediates astrocyte activation in response to the Gram-positive bacterium Staphylococcus aureus. J Neurochem 88:746–758
Farina C, Aloisi F, Meinl E (2007) Astrocytes are active players in cerebral innate immunity. Trends Immunol 28:138–145
Farina C, Krumbholz M, Giese T, Hartmann G, Aloisi F, Meinl E (2005) Preferential expression and function of Toll-like receptor 3 in human astrocytes. J Neuroimmunol 159:12–19
Fitzgerald KA, Rowe DC, Golenbock DT (2004) Endotoxin recognition and signal transduction by the TLR4/MD2-complex. Microbes Infect 6:1361–1367
Gupta D, Kirkland TN, Viriyakosol S, Dziarski R (1996) CD14 is a cell-activating receptor for bacterial peptidoglycan. J Biol Chem 271:23310–23316
Haziot A, Chen S, Ferrero E, Low MG, Silber R, Goyert SM (1988) The monocyte differentiation antigen, CD14, is anchored to the cell membrane by a phosphatidylinositol linkage. J Immunol 141:547–552
Heine H, Kirschning CJ, Lien E, Monks BG, Rothe M, Golenbock DT (1999) Cutting edge:cells that carry A null allele for toll-like receptor 2 are capable of responding to endotoxin. J Immunol 162:6971–6975
Henneke P, Takeuchi O, van Strijp JA, Guttormsen HK, Smith JA, Schromm AB, Espevik TA, Akira S, Nizet V, Kasper DL, Golenbock DT (2001) Novel engagement of CD14 and multiple toll-like receptors by group B streptococci. J Immunol 167:7069–7076
Hertz CJ, Kiertscher SM, Godowski PJ, Bouis DA, Norgard MV, Roth MD, Modlin RL (2001) Microbial lipopeptides stimulate dendritic cell maturation via Toll-like receptor 2. J Immunol 166:2444–2450
Hirschfeld M, Ma Y, Weis JH, Vogel SN, Weis JJ (2000) Cutting edge: repurification of lipopolysaccharide eliminates signaling through both human and murine toll-like receptor 2. J Immunol 165:618–622
Hoebe K, Janssen E, Beutler B (2004) The interface between innate and adaptive immunity. Nat Immunol 5:971–974
Hoshino K, Takeuchi O, Kawai T, Sanjo H, Ogawa T, Takeda Y, Takeda K, Akira S (1999) Cutting edge: Toll-like receptor 4 (TLR4)-deficient mice are hyporesponsive to lipopolysaccharide: evidence for TLR4 as the Lps gene product. J Immunol 162:3749–3752
Hosoi T, Suzuki S, Nomura J, Ono A, Okuma Y, Akira S, Nomura Y (2004) Bacterial DNA induced iNOS expression through MyD88-p38 MAP kinase in mouse primary cultured glial cells. Brain Res Mol Brain Res 124:159–164
Iliev AI, Stringaris AK, Nau R, Neumann H (2004) Neuronal injury mediated via stimulation of microglial toll-like receptor-9 (TLR9). Faseb J 18:412–414
Jung DY, Lee H, Jung BY, Ock J, Lee MS, Lee WH, Suk K (2005) TLR4, but not TLR2, signals autoregulatory apoptosis of cultured microglia: a critical role of IFN-beta as a decision maker. J Immunol 174:6467–6476
Kaisho T, Akira S (2004) Pleiotropic function of Toll-like receptors. Microbes Infect 6:1388–1394
Kielian T (2006) Toll-like receptors in central nervous system glial inflammation and homeostasis. J Neurosci Res 83:711–730
Kielian T, Bearden ED, Baldwin AC, Esen N (2004) IL-1 and TNF-alpha play a pivotal role in the host immune response in a mouse model of Staphylococcus aureus-induced experimental brain abscess. J Neuropathol Exp Neurol 63:381–396
Kielian T, Esen N, Bearden ED (2005) Toll-like receptor 2 (TLR2) is pivotal for recognition of S. aureus peptidoglycan but not intact bacteria by microglia. Glia 49:567–576
Kielian T, Mayes P, Kielian M (2002) Characterization of microglial responses to Staphylococcus aureus: effects on cytokine, costimulatory molecule, and Toll-like receptor expression. J Neuroimmunol 130:86–99
Kigerl KA, Lai W, Rivest S, Hart RP, Satoskar AR, Popovich PG (2007) Toll-like receptor (TLR)-2 and TLR-4 regulate inflammation, gliosis, and myelin sparing after spinal cord injury. J Neurochem 102:37–50
Laflamme N, Echchannaoui H, Landmann R, Rivest S (2003) Cooperation between toll-like receptor 2 and 4 in the brain of mice challenged with cell wall components derived from gram-negative and gram-positive bacteria. Eur J Immunol 33:1127–1138
Laflamme N, Rivest S (2001) Toll-like receptor 4: the missing link of the cerebral innate immune response triggered by circulating gram-negative bacterial cell wall components. FASEB J 15:155–163
Laflamme N, Soucy G, Rivest S (2001) Circulating cell wall components derived from gram-negative, not gram-positive, bacteria cause a profound induction of the gene-encoding Toll-like receptor 2 in the CNS. J Neurochem 79:648–657
Lehnardt S, Lachance C, Patrizi S, Lefebvre S, Follett PL, Jensen FE, Rosenberg PA, Volpe JJ, Vartanian T (2002) The toll-like receptor TLR4 is necessary for lipopolysaccharide-induced oligodendrocyte injury in the CNS. J Neurosci 22:2478–2486
Lehnardt S, Massillon L, Follett P, Jensen FE, Ratan R, Rosenberg PA, Volpe JJ, 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
Lemaitre B, Nicolas E, Michaut L, Reichhart JM, Hoffmann JA (1996) The dorsoventral regulatory gene cassette spatzle/Toll/cactus controls the potent antifungal response in Drosophila adults. Cell 86:973–983
Lien E, Means TK, Heine H, Yoshimura A, Kusumoto S, Fukase K, Fenton MJ, Oikawa M, Qureshi N, Monks B, Finberg RW, Ingalls RR, Golenbock DT (2000) Toll-like receptor 4 imparts ligand-specific recognition of bacterial lipopolysaccharide. J Clin Invest 105:497–504
Ma Y, Haynes RL, Sidman RL, Vartanian T (2007) TLR8: an innate immune receptor in brain, neurons and axons. Cell Cycle 6:2859–2868
Ma Y, Li J, Chiu I, Wang Y, Sloane JA, Lu J, Kosaras B, Sidman RL, Volpe JJ, Vartanian T (2006) Toll-like receptor 8 functions as a negative regulator of neurite outgrowth and inducer of neuronal apoptosis. J Cell Biol 175:209–215
Manukyan M, Triantafilou K, Triantafilou M, Mackie A, Nilsen N, Espevik T, Wiesmuller KH, Ulmer AJ, Heine H (2005) Binding of lipopeptide to CD14 induces physical proximity of CD14, TLR2 and TLR1. Eur J Immunol 35:911–921
Matzinger P (2002) The danger model: a renewed sense of self. Science 296:301–305
Medzhitov R, Janeway C Jr (2000) Innate immunity. N Engl J Med 343:338–344
Medzhitov R, Preston-Hurlburt P, Janeway CA Jr (1997) A human homologue of the Drosophila Toll protein signals activation of adaptive immunity. Nature 388:394–397
Mishra BB, Mishra PK, Teale JM (2006) Expression and distribution of Toll-like receptors in the brain during murine neurocysticercosis. J Neuroimmunol 181:46–56
Mukhopadhyay S, Herre J, Brown GD, Gordon S (2004) The potential for Toll-like receptors to collaborate with other innate immune receptors. Immunology 112:521–530
Nadeau S, Rivest S (2000) Role of microglial-derived tumor necrosis factor in mediating CD14 transcription and nuclear factor kappa B activity in the brain during endotoxemia. J Neurosci 20:3456–3468
Olson JK, Miller SD (2004) Microglia initiate central nervous system innate and adaptive immune responses through multiple TLRs. J Immunol 173:3916–3924
O’Neill LA (2004) TLRs: Professor Mechnikov, sit on your hat. Trends Immunol 25:687–693
O’Neill LA, Bowie AG (2007) The family of five: TIR-domain-containing adaptors in Toll-like receptor signalling. Nat Rev Immunol 7:353–364
Owens T (2005) Toll-like receptors on astrocytes: patterning for immunity. J Neuroimmunol 159:1–2
Palsson-McDermott EM, O’Neill LA (2004) Signal transduction by the lipopolysaccharide receptor, Toll-like receptor-4. Immunology 113:153–162
Pasare C, Medzhitov R (2003) Toll pathway-dependent blockade of CD4 + CD25 + T cell-mediated suppression by dendritic cells. Science 299:1033–1036
Pasare C, Medzhitov R (2004) Toll-like receptors: linking innate and adaptive immunity. Microbes Infect 6:1382–1387
Poltorak A, He X, Smirnova I, Liu MY, Van Huffel C, Du X, Birdwell D, Alejos E, Silva M, Galanos C, Freudenberg M, Ricciardi-Castagnoli P, Layton B, Beutler B (1998a) Defective LPS signaling in C3H/HeJ and C57BL/10ScCr mice: mutations in Tlr4 gene. Science 282:2085–2088
Poltorak A, Smirnova I, He X, Liu MY, Van Huffel C, McNally O, Birdwell D, Alejos E, Silva M, Du X, Thompson P, Chan EK, Ledesma J, Roe B, Clifton S, Vogel SN, Beutler B (1998b) Genetic and physical mapping of the Lps locus: identification of the toll-4 receptor as a candidate gene in the critical region. Blood Cells Mol Dis 24:340–355
Qureshi ST, Lariviere L, Leveque G, Clermont S, Moore KJ, Gros P, Malo D (1999) Endotoxin-tolerant mice have mutations in Toll-like receptor 4 (Tlr4). J Exp Med 189:615–625
Qureshi ST, Medzhitov R (2003) Toll-like receptors and their role in experimental models of microbial infection. Genes Immun 4:87–94
Rasley A, Anguita J, Marriott I (2002) Borrelia burgdorferi induces inflammatory mediator production by murine microglia. J Neuroimmunol 130:22–31
Rivest S (2003) Molecular insights on the cerebral innate immune system. Brain Behav Immun 17:13–19
Saito S, Matsuura M, Tominaga K, Kirikae T, Nakano M (2000) Important role of membrane-associated CD14 in the induction of IFN-beta and subsequent nitric oxide production by murine macrophages in response to bacterial lipopolysaccharide. Eur J Biochem 267:37–45
Saura J (2007) Microglial cells in astroglial cultures: a cautionary note. J Neuroinflammation 4:26
Schroder NW, Morath S, Alexander C, Hamann L, Hartung T, Zahringer U, Gobel UB, Weber JR, Schumann RR (2003) Lipoteichoic acid (LTA) of Streptococcus pneumoniae and Staphylococcus aureus activates immune cells via Toll-like receptor (TLR)-2, lipopolysaccharide-binding protein (LBP), and CD14, whereas TLR-4 and MD-2 are not involved. J Biol Chem 278:15587–15594
Scumpia PO, Kelly KM, Reeves WH, Stevens BR (2005) Double-stranded RNA signals antiviral and inflammatory programs and dysfunctional glutamate transport in TLR3-expressing astrocytes. Glia 52:153–162
Takeda K, Kaisho T, Akira S (2003) Toll-like receptors. Annu Rev Immunol 21:335–376
Takeshita S, Takeshita F, Haddad DE, Janabi N, Klinman DM (2001) Activation of microglia and astrocytes by CpG oligodeoxynucleotides. Neuroreport 12:3029–3032
Takeuchi O, Hoshino K, Kawai T, Sanjo H, Takada H, Ogawa T, Takeda K, Akira S (1999) Differential roles of TLR2 and TLR4 in recognition of gram-negative and gram-positive bacterial cell wall components. Immunity 11:443–451
Tapping RI, Akashi S, Miyake K, Godowski PJ, Tobias PS (2000) Toll-like receptor 4, but not toll-like receptor 2, is a signaling receptor for Escherichia and Salmonella lipopolysaccharides. J Immunol 165:5780–5787
Tsan MF, Gao B (2004) Endogenous ligands of Toll-like receptors. J Leukoc Biol 76:514–519
Underhill DM, Gantner B (2004) Integration of Toll-like receptor and phagocytic signaling for tailored immunity. Microbes Infect 6:1368–1373
Weber JR, Freyer D, Alexander C, Schroder NW, Reiss A, Kuster C, Pfeil D, Tuomanen EI, Schumann RR (2003) Recognition of pneumococcal peptidoglycan: an expanded, pivotal role for LPS binding protein. Immunity 19:269–279
Williams MJ, Rodriguez A, Kimbrell DA, Eldon ED (1997) The 18-wheeler mutation reveals complex antibacterial gene regulation in Drosophila host defense. EMBO J 16:6120–6130
Yamamoto M, Sato S, Hemmi H, Uematsu S, Hoshino K, Kaisho T, Takeuchi O, Takeda K, Akira S (2003) TRAM is specifically involved in the Toll-like receptor 4-mediated MyD88-independent signaling pathway. Nat Immunol 4:1144–1150
Yamamoto M, Takeda K, Akira S (2004) TIR domain-containing adaptors define the specificity of TLR signaling. Mol Immunol 40:861–868
Zekki H, Feinstein DL, Rivest S (2002) 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
Zhang Z, Guo K, Schluesener HJ (2005) The immunostimulatory activity of CpG oligonucleotides on microglial N9 cells is affected by a polyguanosine motif. J Neuroimmunol 161:68–77
Zwijnenburg PJ, van der Poll T, Florquin S, Akira S, Takeda K, Roord JJ, van Furth AM (2003a) Interleukin-18 gene-deficient mice show enhanced defense and reduced inflammation during pneumococcal meningitis. J Neuroimmunol 138:31–37
Zwijnenburg PJ, van der Poll T, Florquin S, Roord JJ, Van Furth AM (2003b) IL-1 receptor type 1 gene-deficient mice demonstrate an impaired host defense against pneumococcal meningitis. J Immunol 170:4724–4730
Acknowledgments
Dr. Kielian’s laboratory is supported by grants from the NIH National Institute of Neurological Disorders and Stroke (RO1s NS055385, NS40730, and NS053487).
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Kielian, T. (2009). Overview of Toll-Like Receptors in the CNS. In: Kielian, T. (eds) Toll-like Receptors: Roles in Infection and Neuropathology. Current Topics in Microbiology and Immunology, vol 336. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-00549-7_1
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