Skip to main content

Advertisement

SpringerLink
Log in

Inflammasomes in inflammatory disorders: the role of TLRs and their interactions with NLRs

  • Review
  • Published:
Seminars in Immunopathology Aims and scope Submit manuscript

Abstract

The innate immune system relies on a variety of pattern recognition receptors (PRRs) such as Toll-like receptors (TLRs) and NOD-like receptors (NLRs) to sense microbial structures that are present in pathogens. Various levels of crosstalk between the TLR and NLR pathways have been described, most notably the description of a molecular scaffold complex, termed the inflammasome, which requires input from both pathways and leads to the activation of the proinflammatory cytokines interleukin (IL)-1β and IL-18. In certain cases, the inflammatory process becomes dysregulated and chronic inflammatory diseases may develop. Understanding the interactions of the TLR and NLR pathways will provide further clues to the pathogeneses of these diseases and to the development of efficient therapies to combat them.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. O’Neill LA (2006) How Toll-like receptors signal: what we know and what we don’t know. Curr Opin Immunol 18(1):3–9

    Article  PubMed  CAS  Google Scholar 

  2. Bowie A, O’Neill LA (2000) The interleukin-1 receptor/Toll-like receptor superfamily: signal generators for pro-inflammatory interleukins and microbial products. J Leukoc Biol 67(4):508–514

    PubMed  CAS  Google Scholar 

  3. Kawai T, Akira S (2006) TLR signaling. Cell Death Differ 13(5):816–825

    Article  PubMed  CAS  Google Scholar 

  4. Creagh EM, O’Neill LA (2006) TLRs, NLRs and RLRs: a trinity of pathogen sensors that co-operate in innate immunity. Trends Immunol 27(8):352–357

    Article  PubMed  CAS  Google Scholar 

  5. Akira S (2006) TLR signaling. Curr Top Microbiol Immunol 311:1–16

    Article  PubMed  CAS  Google Scholar 

  6. Kawai T et al (2004) Interferon-alpha induction through Toll-like receptors involves a direct interaction of IRF7 with MyD88 and TRAF6. Nat Immunol 5(10):1061–1068

    Article  PubMed  CAS  Google Scholar 

  7. Honda K et al (2004) Role of a transductional–transcriptional processor complex involving MyD88 and IRF-7 in Toll-like receptor signaling. Proc Natl Acad Sci U S A 101(43):15416–15421

    Article  PubMed  CAS  Google Scholar 

  8. Takaoka A et al (2005) Integral role of IRF-5 in the gene induction programme activated by Toll-like receptors. Nature 434(7030):243–249

    Article  PubMed  CAS  Google Scholar 

  9. Yamamoto M et al (2003) Role of adaptor TRIF in the MyD88-independent toll-like receptor signaling pathway. Science 301(5633):640–643

    Article  PubMed  CAS  Google Scholar 

  10. Oshiumi H et al (2003) TIR-containing adapter molecule (TICAM)-2, a bridging adapter recruiting to toll-like receptor 4 TICAM-1 that induces interferon-beta. J Biol Chem 278(50):49751–49762

    Article  PubMed  Google Scholar 

  11. Meylan E et al (2004) RIP1 is an essential mediator of Toll-like receptor 3-induced NF-kappa B activation. Nat Immunol 5(5):503–507

    Article  PubMed  CAS  Google Scholar 

  12. Fitzgerald KA et al (2001) Mal (MyD88-adapter-like) is required for Toll-like receptor-4 signal transduction. Nature 413(6851):78–83

    Article  PubMed  CAS  Google Scholar 

  13. Carty M et al (2006) The human adaptor SARM negatively regulates adaptor protein TRIF-dependent Toll-like receptor signaling. Nat Immunol 7(10):1074–1081

    Article  PubMed  CAS  Google Scholar 

  14. Liew FY et al (2005) Negative regulation of toll-like receptor-mediated immune responses. Nat Rev Immunol 5(6):446–458

    Article  PubMed  CAS  Google Scholar 

  15. Ting JP, Kastner DL, Hoffman HM (2006) CATERPILLERs, pyrin and hereditary immunological disorders. Nat Rev Immunol 6(3):183–195

    Article  PubMed  CAS  Google Scholar 

  16. Werts C, Girardin SE, Philpott DJ (2006) TIR, CARD and PYRIN: three domains for an antimicrobial triad. Cell Death Differ 13(5):798–815

    Article  PubMed  CAS  Google Scholar 

  17. Barnich N et al (2005) Membrane recruitment of NOD2 in intestinal epithelial cells is essential for nuclear factor-{kappa}B activation in muramyl dipeptide recognition. J Cell Biol 170(1):21–26

    Article  PubMed  CAS  Google Scholar 

  18. Kummer JA et al (2007) Inflammasome components NALP 1 and 3 show distinct but separate expression profiles in human tissues, suggesting a site-specific role in the inflammatory response. J Histochem Cytochem 55(5):443–452

    Article  PubMed  CAS  Google Scholar 

  19. LeibundGut-Landmann S et al (2004) Mini-review: specificity and expression of CIITA, the master regulator of MHC class II genes. Eur J Immunol 34(6):1513–1525

    Article  PubMed  CAS  Google Scholar 

  20. Chamaillard M, Inohara,N, Nunez G (2004) Battling enteroinvasive bacteria: Nod1 comes to the rescue. Trends Microbiol 12(12):529–532

    Article  PubMed  CAS  Google Scholar 

  21. Girardin SE et al (2003) Nod1 detects a unique muropeptide from gram-negative bacterial peptidoglycan. Science 300(5625):1584–1587

    Article  PubMed  CAS  Google Scholar 

  22. Inohara N et al (2003) Host recognition of bacterial muramyl dipeptide mediated through NOD2. Implications for Crohn’s disease. J Biol Chem 278(8):5509–5512

    Article  PubMed  CAS  Google Scholar 

  23. Girardin SE et al (2003) Nod2 is a general sensor of peptidoglycan through muramyl dipeptide (MDP) detection. J Biol Chem 278(11):8869–8872

    Article  PubMed  CAS  Google Scholar 

  24. Meylan E, Tschopp J (2005) The RIP kinases: crucial integrators of cellular stress. Trends Biochem Sci 30(3):151–159

    Article  PubMed  CAS  Google Scholar 

  25. Kobayashi KS et al (2005) Nod2-dependent regulation of innate and adaptive immunity in the intestinal tract. Science 307(5710):731–734

    Article  PubMed  CAS  Google Scholar 

  26. Girardin SE et al (2001) CARD4/Nod1 mediates NF-kappaB and JNK activation by invasive Shigella flexneri. EMBO Rep 2(8):736–742

    Article  PubMed  CAS  Google Scholar 

  27. Boyden ED, Dietrich WF (2006) Nalp1b controls mouse macrophage susceptibility to anthrax lethal toxin. Nat Genet 38(2):240–244

    Article  PubMed  CAS  Google Scholar 

  28. Agostini L et al (2004) NALP3 forms an IL-1beta-processing inflammasome with increased activity in Muckle–Wells autoinflammatory disorder. Immunity 20(3):319–325

    Article  PubMed  CAS  Google Scholar 

  29. Park JH et al (2007) RICK/RIP2 mediates innate immune responses induced through Nod1 and Nod2 but not TLRs. J Immunol 178(4):2380–2386

    PubMed  CAS  Google Scholar 

  30. Mariathasan S et al (2004) Differential activation of the inflammasome by caspase-1 adaptors ASC and Ipaf. Nature 430(6996):213–218

    Article  PubMed  CAS  Google Scholar 

  31. Sutterwala FS et al (2006) Critical role for NALP3/CIAS1/cryopyrin in innate and adaptive immunity through its regulation of caspase-1. Immunity 24(3):317–327

    Article  PubMed  CAS  Google Scholar 

  32. Watanabe H et al (2007) Activation of the IL-1beta-processing inflammasome is involved in contact hypersensitivity. J Invest Dermatol (in press)

  33. O’Neill LA (2000) The interleukin-1 receptor/Toll-like receptor superfamily: signal transduction during inflammation and host defense. Sci STKE 2000(44):RE1

  34. Martinon F, Tschopp J (2005) NLRs join TLRs as innate sensors of pathogens. Trends Immunol 26(8):447–454

    Article  PubMed  CAS  Google Scholar 

  35. Takeuchi O et al (1999) Differential roles of TLR2 and TLR4 in recognition of gram-negative and gram-positive bacterial cell wall components. Immunity 11(4):443–451

    Article  PubMed  CAS  Google Scholar 

  36. Travassos LH et al (2004) Toll-like receptor 2-dependent bacterial sensing does not occur via peptidoglycan recognition. EMBO Rep 5(10):1000–1006

    Article  PubMed  CAS  Google Scholar 

  37. Fritz JH et al (2005) Synergistic stimulation of human monocytes and dendritic cells by Toll-like receptor 4 and NOD1- and NOD2-activating agonists. Eur J Immunol 35(8):2459–2470

    Article  PubMed  CAS  Google Scholar 

  38. Li J et al (2004) Regulation of IL-8 and IL-1beta expression in Crohn’s disease associated NOD2/CARD15 mutations. Hum Mol Genet 13(16):1715–1725

    Article  PubMed  CAS  Google Scholar 

  39. van Heel DA et al (2005) Synergistic enhancement of Toll-like receptor responses by NOD1 activation. Eur J Immunol 35(8):2471–2476

    Article  PubMed  CAS  Google Scholar 

  40. van Heel DA et al (2005) Muramyl dipeptide and toll-like receptor sensitivity in NOD2-associated Crohn’s disease. Lancet 365(9473):1794–1796

    Article  PubMed  CAS  Google Scholar 

  41. van Heel DA et al (2005) Synergy between TLR9 and NOD2 innate immune responses is lost in genetic Crohn’s disease. Gut 54(11):1553–1557

    Article  PubMed  CAS  Google Scholar 

  42. Uehara A et al (2005) Muramyldipeptide and diaminopimelic acid-containing desmuramylpeptides in combination with chemically synthesized Toll-like receptor agonists synergistically induced production of interleukin-8 in a NOD2- and NOD1-dependent manner, respectively, in human monocytic cells in culture. Cell Microbiol 7(1):53–61

    Article  PubMed  CAS  Google Scholar 

  43. Tada H et al (2005) Synergistic effect of Nod1 and Nod2 agonists with toll-like receptor agonists on human dendritic cells to generate interleukin-12 and T helper type 1 cells. Infect Immun 73(12):7967–7976

    Article  PubMed  CAS  Google Scholar 

  44. Ferwerda G et al (2005) NOD2 and toll-like receptors are nonredundant recognition systems of Mycobacterium tuberculosis. PLoS Pathog 1(3):279–285

    Article  PubMed  CAS  Google Scholar 

  45. Watanabe H et al (2004) Innate immune response in Th1- and Th2-dominant mouse strains. Shock 22(5):460–466

    Article  PubMed  CAS  Google Scholar 

  46. Rosenstiel P et al (2003) TNF-alpha and IFN-gamma regulate the expression of the NOD2 (CARD15) gene in human intestinal epithelial cells. Gastroenterology 124(4):1001–1009

    Article  PubMed  CAS  Google Scholar 

  47. Takahashi Y et al (2006) Up-regulation of NOD1 and NOD2 through TLR4 and TNF-alpha in LPS-treated murine macrophages. J Vet Med Sci 68(5):471–478

    Article  PubMed  CAS  Google Scholar 

  48. Chen CM et al (2004) Reciprocal cross-talk between Nod2 and TAK1 signaling pathways. J Biol Chem 279(24):25876–25882

    Article  PubMed  CAS  Google Scholar 

  49. Kufer TA, Sansonetti PJ (2007) Sensing of bacteria: NOD a lonely job. Curr Opin Microbiol 10(1):62–69

    Article  PubMed  CAS  Google Scholar 

  50. Chin AI et al (2002) Involvement of receptor-interacting protein 2 in innate and adaptive immune responses. Nature 416(6877):190–194

    Article  PubMed  CAS  Google Scholar 

  51. Kobayashi K et al (2002) RICK/Rip2/CARDIAK mediates signalling for receptors of the innate and adaptive immune systems. Nature 416(6877):194–199

    Article  PubMed  CAS  Google Scholar 

  52. Lu C et al (2005) Participation of Rip2 in lipopolysaccharide signaling is independent of its kinase activity. J Biol Chem 280(16):16278–16283

    Article  PubMed  CAS  Google Scholar 

  53. Mariathasan S, Monack DM (2007) Inflammasome adaptors and sensors: intracellular regulators of infection and inflammation. Nat Rev Immunol 7(1):31–40

    Article  PubMed  CAS  Google Scholar 

  54. Kahlenberg JM et al (2005) Potentiation of caspase-1 activation by the P2X7 receptor is dependent on TLR signals and requires NF-kappaB-driven protein synthesis. J Immunol 175(11):7611–7622

    PubMed  CAS  Google Scholar 

  55. Pelegrin P, Surprenant A (2006) Pannexin-1 mediates large pore formation and interleukin-1beta release by the ATP-gated P2X7 receptor. EMBO J 25(21):5071–5082

    Article  PubMed  CAS  Google Scholar 

  56. Solle M et al (2001) Altered cytokine production in mice lacking P2X(7) receptors. J Biol Chem 276(1):125–132

    Article  PubMed  CAS  Google Scholar 

  57. Miao EA et al (2006) Cytoplasmic flagellin activates caspase-1 and secretion of interleukin 1beta via Ipaf. Nat Immunol 7(6):569–575

    Article  PubMed  CAS  Google Scholar 

  58. Miggin SM et al (2007) NF-kappaB activation by the Toll-IL-1 receptor domain protein MyD88 adapter-like is regulated by caspase-1. Proc Natl Acad Sci U S A 104(9):3372–3377

    Article  PubMed  CAS  Google Scholar 

  59. Grenier JM et al (2002) Functional screening of five PYPAF family members identifies PYPAF5 as a novel regulator of NF-kappaB and caspase-1. FEBS Lett 530(1–3):73–78

    Article  PubMed  CAS  Google Scholar 

  60. Wang L (2002) PYPAF7, a novel PYRIN-containing Apaf1-like protein that regulates activation of NF-kappa B and caspase-1-dependent cytokine processing. J Biol Chem 277(33):29874–29880

    Article  PubMed  CAS  Google Scholar 

  61. O’Connor W Jr et al (2003) Cutting edge: CIAS1/cryopyrin/PYPAF1/NALP3/CATERPILLER 1.1 is an inducible inflammatory mediator with NF-kappa B suppressive properties. J Immunol 171(12):6329–6333

    PubMed  CAS  Google Scholar 

  62. Williams KL et al (2005) The CATERPILLER protein monarch-1 is an antagonist of toll-like receptor-, tumor necrosis factor alpha-, and Mycobacterium tuberculosis-induced pro-inflammatory signals. J Biol Chem 280(48):39914–39924

    Article  PubMed  CAS  Google Scholar 

  63. Franchi L et al (2006) Cytosolic flagellin requires Ipaf for activation of caspase-1 and interleukin 1beta in salmonella-infected macrophages. Nat Immunol 7(6):576–582

    Article  PubMed  CAS  Google Scholar 

  64. Berdeli A et al (2005) TLR-2 gene Arg753Gln polymorphism is strongly associated with acute rheumatic fever in children. J Mol Med 83(7):535–541

    Article  PubMed  CAS  Google Scholar 

  65. Ogus AC et al (2004) The Arg753GLn polymorphism of the human toll-like receptor 2 gene in tuberculosis disease. Eur Respir J 23(2):219–223

    Article  PubMed  CAS  Google Scholar 

  66. Moore CE et al (2004) Lack of association between Toll-like receptor 2 polymorphisms and susceptibility to severe disease caused by Staphylococcus aureus. Clin Diagn Lab Immunol 11(6):1194–1197

    Article  PubMed  CAS  Google Scholar 

  67. Kang TJ, Chae GT (2001) Detection of Toll-like receptor 2 (TLR2) mutation in the lepromatous leprosy patients. FEMS Immunol Med Microbiol 31(1):53–58

    Article  PubMed  CAS  Google Scholar 

  68. Agnese DM et al (2002) Human toll-like receptor 4 mutations but not CD14 polymorphisms are associated with an increased risk of gram-negative infections. J Infect Dis 186(10):1522–1525

    Article  PubMed  CAS  Google Scholar 

  69. Child NJ et al (2003) Polymorphisms in Toll-like receptor 4 and the systemic inflammatory response syndrome. Biochem Soc Trans 31(Pt 3):652–653

    Article  PubMed  CAS  Google Scholar 

  70. Minoretti P et al (2006) Effect of the functional toll-like receptor 4 Asp299Gly polymorphism on susceptibility to late-onset Alzheimer’s disease. Neurosci Lett 391(3):147–149

    Article  PubMed  CAS  Google Scholar 

  71. Zheng SL et al (2004) Sequence variants of toll-like receptor 4 are associated with prostate cancer risk: results from the CAncer Prostate in Sweden Study. Cancer Res 64(8):2918–2922

    Article  PubMed  CAS  Google Scholar 

  72. Hawn TR et al (2003) A common dominant TLR5 stop codon polymorphism abolishes flagellin signaling and is associated with susceptibility to legionnaires’ disease. J Exp Med 198(10):1563–1572

    Article  PubMed  CAS  Google Scholar 

  73. Tantisira K et al (2004) Toll-like receptor 6 gene (TLR6): single-nucleotide polymorphism frequencies and preliminary association with the diagnosis of asthma. Genes Immun 5(5):343–346

    Article  PubMed  CAS  Google Scholar 

  74. Abinun M (1995) Ectodermal dysplasia and immunodeficiency. Arch Dis Child 73(2):185

    Article  PubMed  CAS  Google Scholar 

  75. Ku CL et al (2005) Inherited disorders of human Toll-like receptor signaling: immunological implications. Immunol Rev 203:10–20

    Article  PubMed  CAS  Google Scholar 

  76. Picard C et al (2003) Pyogenic bacterial infections in humans with IRAK-4 deficiency. Science 299(5615):2076–2079

    Article  PubMed  CAS  Google Scholar 

  77. Medvedev AE et al (2002) Dysregulation of LPS-induced Toll-like receptor 4-MyD88 complex formation and IL-1 receptor-associated kinase 1 activation in endotoxin-tolerant cells. J Immunol 169(9):5209–5216

    PubMed  Google Scholar 

  78. Jefferies CA, O’Neill LA (2004) Bruton’s tyrosine kinase (Btk)-the critical tyrosine kinase in LPS signalling? Immunol Lett 92(1–2):15–22

    Article  PubMed  CAS  Google Scholar 

  79. Khor CC et al (2007) A Mal functional variant is associated with protection against invasive pneumococcal disease, bacteremia, malaria and tuberculosis. Nat Genet 39(4):523–528

    Article  PubMed  CAS  Google Scholar 

  80. Kiechl S et al (2002) Toll-like receptor 4 polymorphisms and atherogenesis. N Engl J Med 347(3):185–192

    Article  PubMed  CAS  Google Scholar 

  81. Palmer SM et al (2003) The role of innate immunity in acute allograft rejection after lung transplantation. Am J Respir Crit Care Med 168(6):628–632

    Article  PubMed  Google Scholar 

  82. Rudofsky G Jr et al (2004) Asp299Gly and Thr399Ile genotypes of the TLR4 gene are associated with a reduced prevalence of diabetic neuropathy in patients with type 2 diabetes. Diabetes Care 27(1):179–183

    Article  PubMed  CAS  Google Scholar 

  83. Andersen-Nissen E et al (2005) Evasion of Toll-like receptor 5 by flagellated bacteria. Proc Natl Acad Sci U S A 102(26):9247–9252

    Article  PubMed  CAS  Google Scholar 

  84. Andersen-Nissen E et al (2007) A conserved surface on Toll-like receptor 5 recognizes bacterial flagellin. J Exp Med 204(2):393–403

    Article  PubMed  CAS  Google Scholar 

  85. Fortune SM et al (2004) Mycobacterium tuberculosis inhibits macrophage responses to IFN-gamma through myeloid differentiation factor 88-dependent and -independent mechanisms. J Immunol 172(10):6272–6280

    PubMed  CAS  Google Scholar 

  86. Rosenstiel P, Till A, Schreiber S (2007) NOD-like receptors and human diseases. Microbes Infect 9(5):648–657

    Article  PubMed  CAS  Google Scholar 

  87. Dinarello CA (1996) Biologic basis for interleukin-1 in disease. Blood 87(6):2095–2147

    PubMed  CAS  Google Scholar 

  88. Cook DN, Pisetsky DS, Schwartz DA (2004) Toll-like receptors in the pathogenesis of human disease. Nat Immunol 5(10):975–979

    Article  PubMed  CAS  Google Scholar 

  89. Trinchieri G, Sher A (2007) Cooperation of Toll-like receptor signals in innate immune defence. Nat Rev Immunol 7(3):179–190

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. School of Biochemistry and Immunology, Trinity College Dublin, Dublin, Ireland

    Christine E. Becker & Luke A. J. O’Neill

Authors
  1. Christine E. Becker
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Luke A. J. O’Neill
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Christine E. Becker.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Becker, C.E., O’Neill, L.A.J. Inflammasomes in inflammatory disorders: the role of TLRs and their interactions with NLRs. Semin Immunopathol 29, 239–248 (2007). https://doi.org/10.1007/s00281-007-0081-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00281-007-0081-4

Keywords

Search

Navigation