Immune response - TLR signaling pathways

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TLR signaling pathways

Both gram-positive and gram-negative bacteria and their cell wall components activate innate immune system of the host and induce secretion of proinflammatory molecules, mainly chemokines and cytokines [1]. Toll-like receptors (TLRs) initiate signaling cascades through recognition of a variety of microbial components, thus serving as an important link between innate and adaptive immune responses. Each TLR recognizes distinct ligands [2]. TLR2 agonists include peptidoglycan, lipoproteins, and lipopeptides from Gram-positive bacteria, mycobacterial lipoarabinomannan, mycoplasma lipopeptides [3], but only when present as a heterodimer in combination with either TLR1 or TLR6 [4]. TLR3 and TLR5 mediate cell activation by double-stranded viral RNA and bacterial flagellin, respectively [3]. TLR9 responds to unmethylated CpG motif in bacterial and viral DNA [3], [4]. TLR4 is essential in the respective recognition of lipopolysaccharide (LPS) [4], lipoteichoic acid [5] and some other substrates [6], [7], [8]. A number of microbial substrates are known for TLR7 and TLR8 [8], [9], [10].

The main TLR-mediated immune response pathway, which is common for all TLRs, is Myeloid differentiation primary response gene 88 (MyD88)-dependent activation of Nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor (NF-kB) and c-Jun, transcription regulators of number of chemokines and cytokines responsible for cellular immune response. The main steps of NF-kB activation involve MyD88/ Interleukin-1 receptor-associated kinases (IRAK)/ TNF receptor-associated factor 6 (TRAF6)/ Mitogen-activated protein kinase kinase kinase 14 (NIK)/ Inhibitor of kappa light polypeptide gene enhancer in B-cells (IKK)/ NF-kB signal transduction [1]. C-Jun activation proceeds throw MyD88/ IRAK/ TRAF6/ Mitogen-activated protein kinase kinase kinase 7 interacting protein 1 (TAB)/ Mitogen-activated protein kinase kinase kinase 7 (TAK) cascade [4], [11]. TLR family members can induce autophagy through direct activation of Beclin 1 by MyD88 [12].

Besides MyD88, some TLRs use alternative adaptor proteins to induce NF-kB and c-Jun activation, such as Toll-interleukin 1 receptor domain containing adaptor protein (TIRAP) [4], [13]. Certain types of TLRs (for example, TLR3 and TLR4) demonstrate also other response pathways, which are specific for them.

References:

  1. Wang Q, Dziarski R, Kirschning CJ, Muzio M, Gupta D
    Micrococci and peptidoglycan activate TLR2-->MyD88-->IRAK-->TRAF-->NIK-->IKK-->NF-kappaB signal transduction pathway that induces transcription of interleukin-8. Infection and immunity 2001 Apr;69(4):2270-6
  2. Meylan E, Burns K, Hofmann K, Blancheteau V, Martinon F, Kelliher M, Tschopp J
    RIP1 is an essential mediator of Toll-like receptor 3-induced NF-kappa B activation. Nature immunology 2004 May;5(5):503-7
  3. Medvedev AE, Lentschat A, Wahl LM, Golenbock DT, Vogel SN
    Dysregulation of LPS-induced Toll-like receptor 4-MyD88 complex formation and IL-1 receptor-associated kinase 1 activation in endotoxin-tolerant cells. Journal of immunology (Baltimore, Md. : 1950) 2002 Nov 1;169(9):5209-16
  4. Harte MT, Haga IR, Maloney G, Gray P, Reading PC, Bartlett NW, Smith GL, Bowie A, O'Neill LA
    The poxvirus protein A52R targets Toll-like receptor signaling complexes to suppress host defense. The Journal of experimental medicine 2003 Feb 3;197(3):343-51
  5. Takeuchi O, Akira S
    Toll-like receptors; their physiological role and signal transduction system. International immunopharmacology 2001 Apr;1(4):625-35
  6. Guillot L, Balloy V, McCormack FX, Golenbock DT, Chignard M, Si-Tahar M
    Cutting edge: the immunostimulatory activity of the lung surfactant protein-A involves Toll-like receptor 4. Journal of immunology (Baltimore, Md. : 1950) 2002 Jun 15;168(12):5989-92
  7. Malley R, Henneke P, Morse SC, Cieslewicz MJ, Lipsitch M, Thompson CM, Kurt-Jones E, Paton JC, Wessels MR, Golenbock DT
    Recognition of pneumolysin by Toll-like receptor 4 confers resistance to pneumococcal infection. Proceedings of the National Academy of Sciences of the United States of America 2003 Feb 18;100(4):1966-71
  8. Lee J, Chuang TH, Redecke V, She L, Pitha PM, Carson DA, Raz E, Cottam HB
    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 2003 May 27;100(11):6646-51
  9. Ito T, Amakawa R, Kaisho T, Hemmi H, Tajima K, Uehira K, Ozaki Y, Tomizawa H, Akira S, Fukuhara S
    Interferon-alpha and interleukin-12 are induced differentially by Toll-like receptor 7 ligands in human blood dendritic cell subsets. The Journal of experimental medicine 2002 Jun 3;195(11):1507-12
  10. Heil F, Ahmad-Nejad P, Hemmi H, Hochrein H, Ampenberger F, Gellert T, Dietrich H, Lipford G, Takeda K, Akira S, Wagner H, Bauer S
    The Toll-like receptor 7 (TLR7)-specific stimulus loxoribine uncovers a strong relationship within the TLR7, 8 and 9 subfamily. European journal of immunology 2003 Nov;33(11):2987-97
  11. Lynn DJ, Lloyd AT, O'Farrelly C
    In silico identification of components of the Toll-like receptor (TLR) signaling pathway in clustered chicken expressed sequence tags (ESTs). Veterinary immunology and immunopathology 2003 Jun 20;93(3-4):177-84
  12. Shi CS, Kehrl JH
    MyD88 and Trif target Beclin 1 to trigger autophagy in macrophages. The Journal of biological chemistry 2008 Nov 28;283(48):33175-82
  13. Matsumoto M, Funami K, Oshiumi H, Seya T
    Toll-like receptor 3: a link between toll-like receptor, interferon and viruses. Microbiology and immunology 2004;48(3):147-54

  1. Wang Q, Dziarski R, Kirschning CJ, Muzio M, Gupta D
    Micrococci and peptidoglycan activate TLR2-->MyD88-->IRAK-->TRAF-->NIK-->IKK-->NF-kappaB signal transduction pathway that induces transcription of interleukin-8. Infection and immunity 2001 Apr;69(4):2270-6
  2. Meylan E, Burns K, Hofmann K, Blancheteau V, Martinon F, Kelliher M, Tschopp J
    RIP1 is an essential mediator of Toll-like receptor 3-induced NF-kappa B activation. Nature immunology 2004 May;5(5):503-7
  3. Medvedev AE, Lentschat A, Wahl LM, Golenbock DT, Vogel SN
    Dysregulation of LPS-induced Toll-like receptor 4-MyD88 complex formation and IL-1 receptor-associated kinase 1 activation in endotoxin-tolerant cells. Journal of immunology (Baltimore, Md. : 1950) 2002 Nov 1;169(9):5209-16
  4. Harte MT, Haga IR, Maloney G, Gray P, Reading PC, Bartlett NW, Smith GL, Bowie A, O'Neill LA
    The poxvirus protein A52R targets Toll-like receptor signaling complexes to suppress host defense. The Journal of experimental medicine 2003 Feb 3;197(3):343-51
  5. Takeuchi O, Akira S
    Toll-like receptors; their physiological role and signal transduction system. International immunopharmacology 2001 Apr;1(4):625-35
  6. Guillot L, Balloy V, McCormack FX, Golenbock DT, Chignard M, Si-Tahar M
    Cutting edge: the immunostimulatory activity of the lung surfactant protein-A involves Toll-like receptor 4. Journal of immunology (Baltimore, Md. : 1950) 2002 Jun 15;168(12):5989-92
  7. Malley R, Henneke P, Morse SC, Cieslewicz MJ, Lipsitch M, Thompson CM, Kurt-Jones E, Paton JC, Wessels MR, Golenbock DT
    Recognition of pneumolysin by Toll-like receptor 4 confers resistance to pneumococcal infection. Proceedings of the National Academy of Sciences of the United States of America 2003 Feb 18;100(4):1966-71
  8. Lee J, Chuang TH, Redecke V, She L, Pitha PM, Carson DA, Raz E, Cottam HB
    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 2003 May 27;100(11):6646-51
  9. Ito T, Amakawa R, Kaisho T, Hemmi H, Tajima K, Uehira K, Ozaki Y, Tomizawa H, Akira S, Fukuhara S
    Interferon-alpha and interleukin-12 are induced differentially by Toll-like receptor 7 ligands in human blood dendritic cell subsets. The Journal of experimental medicine 2002 Jun 3;195(11):1507-12
  10. Heil F, Ahmad-Nejad P, Hemmi H, Hochrein H, Ampenberger F, Gellert T, Dietrich H, Lipford G, Takeda K, Akira S, Wagner H, Bauer S
    The Toll-like receptor 7 (TLR7)-specific stimulus loxoribine uncovers a strong relationship within the TLR7, 8 and 9 subfamily. European journal of immunology 2003 Nov;33(11):2987-97
  11. Lynn DJ, Lloyd AT, O'Farrelly C
    In silico identification of components of the Toll-like receptor (TLR) signaling pathway in clustered chicken expressed sequence tags (ESTs). Veterinary immunology and immunopathology 2003 Jun 20;93(3-4):177-84
  12. Shi CS, Kehrl JH
    MyD88 and Trif target Beclin 1 to trigger autophagy in macrophages. The Journal of biological chemistry 2008 Nov 28;283(48):33175-82
  13. Matsumoto M, Funami K, Oshiumi H, Seya T
    Toll-like receptor 3: a link between toll-like receptor, interferon and viruses. Microbiology and immunology 2004;48(3):147-54

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