Toll-Like receptors and opportunities for new sepsis therapeutics

Current Infectious Disease Reports

Volumn 14, Issue 5, 2012, Pages 455-461

  Boyd, John H ^a  

^a UNIVERSITY OF BRITISH COLUMBIA   (Canada)

Author keywords

DAMP; Innate immunity; PAMP; Sepsis; Toll like receptor

Indexed keywords

ERITORAN; IMMUNOGLOBULIN ENHANCER BINDING PROTEIN; INTERLEUKIN 6; METHYLPREDNISOLONE; PLACEBO; RESATORVID; TOLL LIKE RECEPTOR; TOLL LIKE RECEPTOR 3; TOLL LIKE RECEPTOR 4; TOLL LIKE RECEPTOR 5; TOLL LIKE RECEPTOR 7; TOLL LIKE RECEPTOR 9;

ANTIINFLAMMATORY ACTIVITY; DRUG HALF LIFE; DRUG MEGADOSE; DRUG RESPONSE; DRUG TARGETING; ENDOTOXEMIA; HUMAN; INFLAMMATION; INNATE IMMUNITY; NONHUMAN; PHASE 2 CLINICAL TRIAL (TOPIC); PHASE 3 CLINICAL TRIAL (TOPIC); PROTEIN ANALYSIS; PROTEIN FUNCTION; PROTEIN TARGETING; RANDOMIZED CONTROLLED TRIAL (TOPIC); REVIEW; SEPSIS; SEPTIC SHOCK; SIGNAL TRANSDUCTION;

EID: 84870536892     PISSN: 15233847     EISSN: 15343146     Source Type: Journal    
DOI: 10.1007/s11908-012-0273-5     Document Type: Review

References (85)

1. Akira S. Toll-like receptors: lessons from knockout mice. Biochem Soc Trans. 2000;28(5):551-6.
2. Akira S, Takeda K. Toll-like receptor signalling. Nat Rev Immunol. 2004;4(7):499-511.
3. Akira S, Takeda K, Kaisho T. Toll-like receptors: critical proteins linking innate and acquired immunity. Nat Immunol. 2001;2 (8):675-80.
4. Jenner RG, Young RA. Insights into host responses against pathogens from transcriptional profiling. Nat Rev Microbiol. 2005;3 (4):281-94.
5. MacCallum DM. Massive induction of innate immune response to Candida albicans in the kidney in a murine intravenous challenge model. FEMS Yeast Res. 2009;9(7):1111-22.
6. Pandya U, Sinha M, Luxon BA, Watson DA, Niesel DW. Global transcription profiling and virulence potential of Streptococcus pneumoniae after serial passage. Gene. 2009;443(1-2):22-31.
7. Tang BM, McLean AS, Dawes IW, Huang SJ, Lin RC. Geneexpression profiling of peripheral blood mononuclear cells in sepsis. Crit Care Med. 2009;37(3):882-8.
8. Polpitiya AD, McDunn JE, Burykin A, Ghosh BK, Cobb JP. Using systems biology to simplify complex disease: immune cartography. Crit Care Med. 2009;37(1 Suppl):S16-21.
9. Russel JA. The current management of septic shock. Minerva Med. 2008;99(5):431-58.
10. Sutherland AM, Walley KR, Manocha S, Russell JA. The association of interleukin 6 haplotype clades with mortality in critically ill adults. Arch Intern Med. 2005;165(1):75-82.
11. van der Poll T, Meijers JC. Systemic inflammatory response syndrome and compensatory anti-inflammatory response syndrome in sepsis. J Innate Immun. 2(5):379-380.
12. Adib-Conquy M, Cavaillon JM. Compensatory anti-inflammatory response syndrome. Thromb Haemost. 2009;101(1):36-47.
13. Ward NS, Casserly B, Ayala A. The compensatory antiinflammatory response syndrome (CARS) in critically ill patients. Clin Chest Med. 2008;29(4):617-25. viii.
14. Lemaitre B, Nicolas E, Michaut L, Reichhart JM, Hoffmann JA. The dorsoventral regulatory gene cassette spatzle/Toll/cactus controls the potent antifungal response in Drosophila adults. Cell. 1996;86(6):973-83.
15. Muzio M, Bosisio D, Polentarutti N, D'Amico G, Stoppacciaro A, Mancinelli R, et al. Differential expression and regulation of tolllike receptors (TLR) in human leukocytes: selective expression of TLR3 in dendritic cells. J Immunol. 2000;164(11):5998-6004.
16. Rossi D, Zlotnik A. The biology of chemokines and their receptors. Annu Rev Immunol. 2000;18:217-42.
17. Chong AJ, Shimamoto A, Hampton CR, Takayama H, Spring DJ, Rothnie CL, et al. Toll-like receptor 4 mediates ischemia/reperfusion injury of the heart. J Thorac Cardiovasc Surg. 2004;128(2):170-9.
18. Cook DN, Pisetsky DS, Schwartz DA. Toll-like receptors in the pathogenesis of human disease. Nat Immunol. 2004;5(10):975-9.
19. Abreu MT, Fukata M, Arditi M. TLR signaling in the gut in health and disease. J Immunol. 2005;174(8):4453-60.
20. Caso JR, Pradillo JM, Hurtado O, Lorenzo P, Moro MA, Lizasoain I. Toll-like receptor 4 is involved in brain damage and inflammation after experimental stroke. Circulation. 2007;115(12):1599-608.
21. Akira S, Uematsu S, Takeuchi O. Pathogen recognition and innate immunity. Cell. 2006;124(4):783-801.
22. Ohashi K, Burkart V, Flohe S, Kolb H. Cutting edge: heat shock protein 60 is a putative endogenous ligand of the toll-like receptor-4 complex. J Immunol. 2000;164(2):558-61.
23. Vabulas RM, Braedel S, Hilf N, Singh-Jasuja H, Herter S, Ahmad-Nejad P, et al. The endoplasmic reticulum-resident heat shock protein Gp96 activates dendritic cells via the Toll-like receptor 2/4 pathway. J Biol Chem. 2002;277(23):20847-53.
24. Vabulas RM, Ahmad-Nejad P, Ghose S, Kirschning CJ, Issels RD, Wagner H. HSP70 as endogenous stimulus of the Toll/interleukin-1 receptor signal pathway. J Biol Chem. 2002;277(17):15107-12.
25. Vabulas RM, Wagner H, Schild H. Heat shock proteins as ligands of toll-like receptors. Curr Top Microbiol Immunol. 2002;270:169-84.
26. Takeda K, Akira S. Toll-like receptors in innate immunity. Int Immunol. 2005;17(1):1-14.
27. Termeer C, Benedix F, Sleeman J, Fieber C, Voith U, Ahrens T, et al. Oligosaccharides of Hyaluronan activate dendritic cells via tolllike receptor 4. J Exp Med. 2002;195(1):99-111.
28. Gombos T, Forhecz Z, Pozsonyi Z, Janoskuti L, Prohaszka Z. Interaction of serum 70-kDa heat shock protein levels and HspA1B (+1267) gene polymorphism with disease severity in patients with chronic heart failure. Cell Stress Chaperones. 2008;13(2):199-206.
29. de Jong PR, Schadenberg AW, Jansen NJ, Prakken BJ. Hsp70 and cardiac surgery: molecular chaperone and inflammatory regulator with compartmentalized effects. Cell Stress Chaperones. 2009;14 (2):117-31.
30. Mathur S, Walley KR, Wang Y, Indrambarya T, Boyd JH. Extracellular heat shock protein 70 induces cardiomyocyte inflammation and contractile dysfunction via TLR2. Circ J. 2011;75 (10):2445-52.
31. Frantz S, Kelly RA, Bourcier T. Role of TLR-2 in the activation of nuclear factor kappaB by oxidative stress in cardiac myocytes. J Biol Chem. 2001;276(7):5197-203.
32. Slack JL, Schooley K, Bonnert TP, Mitcham JL, Qwarnstrom EE, Sims JE, et al. Identification of two major sites in the type I interleukin-1 receptor cytoplasmic region responsible for coupling to pro-inflammatory signaling pathways. J Biol Chem. 2000;275 (7):4670-8.
33. Akira S, Yamamoto M, Takeda K. Role of adapters in Toll-like receptor signalling. Biochem Soc Trans. 2003;31(Pt 3):637-42.
34. Palsson-McDermott EM, O'Neill LA. Signal transduction by the lipopolysaccharide receptor, Toll-like receptor-4. Immunology. 2004;113(2):153-62.
35. Ghosh S, Karin M. Missing pieces in the NF-kappaB puzzle. Cell. 2002;109(Suppl):S81-96.
36. Kariko K, Weissman D, Welsh FA. Inhibition of toll-like receptor and cytokine signaling-A unifying theme in ischemic tolerance. J Cereb Blood Flow Metab. 2004;24(11):1288-304.
37. Fan H, Cook JA. Molecular mechanisms of endotoxin tolerance. J Endotoxin Res. 2004;10(2):71-84.
38. Wald D, Qin J, Zhao Z, Qian Y, Naramura M, Tian L, et al. SIGIRR, a negative regulator of Toll-like receptor-interleukin 1 receptor signaling. Nat Immunol. 2003;4(9):920-7.
39. Brint EK, Xu D, Liu H, Dunne A, McKenzie AN, O'Neill LA, et al. ST2 is an inhibitor of interleukin 1 receptor and Toll-like receptor 4 signaling and maintains endotoxin tolerance. Nat Immunol. 2004;5(4):373-9.
40. Burns K, Janssens S, Brissoni B, Olivos N, Beyaert R, Tschopp J. 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. 2003;197(2):263-8.
41. Janssens S, Burns K, Vercammen E, Tschopp J, Beyaert R. MyD88S, a splice variant of MyD88, differentially modulates NF-kappaB-And AP-1-dependent gene expression. FEBS Lett. 2003;548(1-3):103-7.
42. Zhang G, Ghosh S. Negative regulation of toll-like receptormediated signaling by Tollip. J Biol Chem. 2002;277(9):7059-65.
43. Jiang X, Zhu D, Okagaki P, Lipsky R, Wu X, Banaudha K, et al. N-methyl-D-Aspartate and TrkB receptor activation in cerebellar granule cells: an in vitro model of preconditioning to stimulate intrinsic survival pathways in neurons. Ann N Y Acad Sci. 2003;993:134-45. discussion 159-160.
44. Ha T, Hua F, Liu X, Ma J, McMullen JR, Shioi T, et al. Lipopolysaccharide-induced myocardial protection against ischaemia/reperfusion injury is mediated through a PI3K/Akt-dependent mechanism. Cardiovasc Res. 2008;78(3):546-53.
45. Klaschik S, Tross D, Klinman DM. Inductive and suppressive networks regulate TLR9-dependent gene expression in vivo. J Leukoc Biol. 2009;85(5):788-95.
46. Tross D, Petrenko L, Klaschik S, Zhu Q, Klinman DM. Global changes in gene expression and synergistic interactions induced by TLR9 and TLR3. Mol Immunol. 2009;46(13):2557-64.
47. Yeo SJ, Yoon JG, Hong SC, Yi AK. CpG DNA induces self and cross-hyporesponsiveness of RAW264.7 cells in response to CpG DNA and lipopolysaccharide: alterations in IL-1 receptorassociated kinase expression. J Immunol. 2003;170(2):1052-61.
48. Mathur S, Walley KR, Boyd JH. The Toll-like receptor 9 ligand CPG-C attenuates acute inflammatory cardiac dysfunction. Shock. 2011;36(5):478-83. This manuscripts details the use of the TLR9 agonist CpG as a therapeutic option for severe acute cardiovascular failure due to both endotoxin and ischemia.
49. Brun-Buisson C, Doyon F, Carlet J, Dellamonica P, Gouin F, Lepoutre A, et al. Incidence, risk factors, and outcome of severe sepsis and septic shock in adults. A multicenter prospective study in intensive care units. French ICU Group for Severe Sepsis. JAMA. 1995;274(12):968-74.
50. Wang HE, Shapiro NI, Angus DC, Yealy DM. National estimates of severe sepsis in United States emergency departments. Crit Care Med. 2007;35(8):1928-36.
51. Ziegler EJ, McCutchan JA, Fierer J, Glauser MP, Sadoff JC, Douglas H, et al. Treatment of gram-negative bacteremia and shock with human antiserum to a mutant Escherichia coli. N Engl J Med. 1982;307(20):1225-30.
52. Angus DC, Birmingham MC, Balk RA, Scannon PJ, Collins D, Kruse JA, et al. E5 murine monoclonal antiendotoxin antibody in gram-negative sepsis: a randomized controlled trial. E5 Study Investigators. JAMA. 2000;283(13):1723-30.
53. Albertson TE, Panacek EA,MacArthur RD, Johnson SB, Benjamin E, Matuschak GM, et al. Multicenter evaluation of a human monoclonalantibody to Enterobacteriaceae common antigen in patients with Gram-negative sepsis. Crit Care Med. 2003;31(2):419-27.
54. Kaisho T, Akira S. Toll-like receptor function and signaling. J Allergy Clin Immunol. 2006;117(5):979-87. quiz 988.
55. Kawai T, Akira S. TLR signaling. Semin Immunol. 2007;19(1):24-32.
56. Kawai T, Akira S. Signaling to NF-kappaB by Toll-like receptors. Trends Mol Med. 2007;13(11):460-9.
57. Ii M, Matsunaga N, Hazeki K, Nakamura K, Takashima K, Seya T, et al. A novel cyclohexene derivative, ethyl (6R)-6-[N-(2-Chloro-4-fluorophenyl) sulfamoyl]cyclohex-1-ene-1-carboxylate (TAK-242), selectively inhibits toll-like receptor 4-mediated cytokine production through suppression of intracellular signaling. Mol Pharmacol. 2006;69(4):1288-95.
58. Yamada M, Ichikawa T, Yamano T, Kikumoto F, Nishikimi Y, Tamura N, et al. Optically active cyclohexene derivative as a new antisepsis agent: an efficient synthesis of ethyl (6R)-6-[N-(2-chloro-4-fluorophenyl)sulfamoyl]cyclohex-1-ene- 1-carboxylate (TAK-242). Chem Pharm Bull(Tokyo). 2006;54(1):58-62.
59. Sha T, Sunamoto M, Kitazaki T, Sato J, Ii M, Iizawa Y. Therapeutic effects of TAK-242, a novel selective Toll-like receptor 4 signal transduction inhibitor, in mouse endotoxin shock model. Eur J Pharmacol. 2007;571(2-3):231-9.
60. Kawamoto T, Ii M, Kitazaki T, Iizawa Y, Kimura H. TAK-242 selectively suppresses Toll-like receptor 4-signaling mediated by the intracellular domain. Eur J Pharmacol. 2008;584(1):40-8.
61. KunoM, Nemoto K, Ninomiya N, Inagaki E, KubotaM,Matsumoto T, et al. The novel selective toll-like receptor 4 signal transduction inhibitor tak-242 prevents endotoxaemia in conscious Guinea-pigs. Clin Exp Pharmacol Physiol. 2009;36(5-6):589-93.
62. Takashima K, Matsunaga N, Yoshimatsu M, Hazeki K, Kaisho T, Uekata M, et al. Analysis of binding site for the novel smallmolecule TLR4 signal transduction inhibitor TAK-242 and its therapeutic effect on mouse sepsis model. Br J Pharmacol. 2009;157(7):1250-62.
63. Rice TW, Wheeler AP, Bernard GR, Vincent JL, Angus DC, Aikawa N, et al. A randomized, double-blind, placebo-controlled trial of TAK-242 for the treatment of severe sepsis. Crit Care Med. 2010;38(8):1685-94. This phase III trial using the small molecule inhibitor of TLR4 signaling TAK-242 failed to demonstrate an effect in septic shock.
64. Matsunaga N, Tsuchimori N, Matsumoto T, Ii M. TAK-242 (resatorvid), a small-molecule inhibitor of Toll-like receptor (TLR) 4 signaling, binds selectively to TLR4 and interferes with interactions between TLR4 and its adaptor molecules. Mol Pharmacol. 2011;79(1):34-41.
65. Kaneko K, Ueda R, Kikuchi K, Sano Y, Yoshimura T. Quantitative determination of a potent lipopolysaccharide antagonist, E5564, in rat and dog plasma by high-performance liquid chromatography with fluorescence detection. J Chromatogr B Biomed Sci Appl. 1999;736(1-2):67-75.
66. Okamura Y, Watari M, Jerud ES, Young DW, Ishizaka ST, Rose J, et al. The extra domain A of fibronectin activates Toll-like receptor 4. J Biol Chem. 2001;276(13):10229-33.
67. Lynn M, Rossignol DP, Wheeler JL, Kao RJ, Perdomo CA, Noveck R, et al. Blocking of responses to endotoxin by E5564 in healthy volunteers with experimental endotoxemia. J Infect Dis. 2003;187(4):631-9.
68. Mullarkey M, Rose JR, Bristol J, Kawata T, Kimura A, Kobayashi S, et al. Inhibition of endotoxin response by e5564, a novel Tolllike receptor 4-directed endotoxin antagonist. J Pharmacol Exp Ther. 2003;304(3):1093-102.
69. Wong YN, Rossignol D, Rose JR, Kao R, Carter A, Lynn M. Safety, pharmacokinetics, and pharmacodynamics of E5564, a lipid A antagonist, during an ascending single-dose clinical study. J Clin Pharmacol. 2003;43(7):735-42.
70. Rossignol DP, Wasan KM, Choo E, Yau E, Wong N, Rose J, et al. Safety, pharmacokinetics, pharmacodynamics, and plasma lipoprotein distribution of eritoran (E5564) during continuous intravenous infusion into healthy volunteers. Antimicrob Agents Chemother. 2004;48(9):3233-40.
71. Savov JD, Brass DM, Lawson BL, McElvania-Tekippe E, Walker JK, Schwartz DA. Toll-like receptor 4 antagonist (E5564) prevents the chronic airway response to inhaled lipopolysaccharide. Am J Physiol Lung Cell Mol Physiol. 2005;289(2):L329-37.
72. Czeslick E, Struppert A, Simm A, Sablotzki A. E5564 (Eritoran) inhibits lipopolysaccharide-induced cytokine production in human blood monocytes. Inflamm Res. 2006;55(11):511-5.
73. Sutherland AM, Walley KR, Russell JA. Polymorphisms in CD14, mannose-binding lectin, and Toll-like receptor-2 are associated with increased prevalence of infection in critically ill adults. Crit Care Med. 2005;33(3):638-44.
74. Wurfel MM, Gordon AC, Holden TD, Radella F, Strout J, Kajikawa O, et al. Toll-like receptor 1 polymorphisms affect innate immune responses and outcomes in sepsis. Am J Respir Crit Care Med. 2008;178(7):710-20.
75. Shaw DM, Sutherland AM, Russell JA, Lichtenstein SV, Walley KR. Novel polymorphism of interleukin-18 associated with greater inflammation after cardiac surgery. Crit Care. 2009;13(1):R9.
76. Nakada TA, Russell JA, Boyd JH, Aguirre-Hernandez R, Thain KR, Thair SA, et al. beta2-Adrenergic receptor gene polymorphism is associated with mortality in septic shock. Am J Respir Crit Care Med. 2010;181(2):143-9.
77. Tidswell M, Tillis W, Larosa SP, Lynn M, Wittek AE, Kao R, et al. Phase 2 trial of eritoran tetrasodium (E5564), a toll-like receptor 4 antagonist, in patients with severe sepsis. Crit Care Med. 2010;38 (1):72-83. This manuscript described the results of a large phase II trial using the TLR4 antogonist E5564, showing promising results in the sickest patients (high APACHEII score).
78. Sprung CL, Caralis PV, Marcial EH, Pierce M, Gelbard MA, Long WM, et al. The effects of high-dose corticosteroids in patients with septic shock. A prospective, controlled study. N Engl J Med. 1984;311(18):1137-43.
79. Effect of high-dose glucocorticoid therapy on mortality in patients with clinical signs of systemic sepsis. The Veterans Administration Systemic Sepsis Cooperative Study Group. N Engl J Med. 1987;317(11):659-665.
80. Bone RC, Fisher Jr. CJ, Clemmer TP, Slotman GJ, Metz CA, Balk RA. A controlled clinical trial of high-dose methylprednisolone in the treatment of severe sepsis and septic shock. N Engl J Med. 1987;317(11):653-8.
81. Abraham E, Wunderink R, Silverman H, Perl TM, Nasraway S, Levy H, et al. Efficacy and safety of monoclonal antibody to human tumor necrosis factor alpha in patients with sepsis syndrome. A randomized, controlled, double-blind, multicenter clinical trial. TNF-Alpha MAb Sepsis Study Group. JAMA. 1995;273 (12):934-41.
82. Cohen J, Carlet J. INTERSEPT: an international, multicenter, placebo-controlled trial of monoclonal antibody to human tumor necrosis factor-Alpha in patients with sepsis. International Sepsis Trial Study Group. Crit Care Med. 1996;24(9):1431-40.
83. Abraham E, Glauser MP, Butler T, Garbino J, Gelmont D, Laterre PF, et al. p55 Tumor necrosis factor receptor fusion protein in the treatment of patients with severe sepsis and septic shock. A randomized controlled multicenter trial. Ro 45-2081 Study Group. JAMA. 1997;277(19):1531-8.
84. Abraham E, Laterre PF, Garbino J, Pingleton S, Butler T, Dugernier T, et al. Lenercept (p55 tumor necrosis factor receptor fusion protein) in severe sepsis and early septic shock: a randomized, double-blind, placebo-controlled, multicenter phase III trial with 1,342 patients. Crit Care Med. 2001;29(3):503-10.
85. Parmar A, Langenberg C, Wan L, et al. Epidemiology of septic acute kidney injury. Curr Drug Targets. 2009;10:1169-78.