Current knowledge and future directions of TLR and NOD signaling in sepsis

Chalupka AN, Talmor D. The economics of sepsis. Crit Care Clin. 2012;28:57–76. Dellinger RP, Levy MM, Rhodes A, Annane D, Gerlach H, Opal SM, et al. Surviving sepsis campaign: international guidelines for management of severe sepsis and septic shock: 2012. Intensive Care Med. 2013;39:165–228. American College of Chest Physicians/Society of Critical Care Medicine Consensus Conference. Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. Crit Care Med. 1992;20:864–874. Levy MM, Fink MP, Marshall JC, Abraham E, Angus D, Cook D, et al. SCCM/ESICM/ACCP/ATS/SIS international sepsis definitions conference. Crit Care Med. 2003;31:1250–1256. Medzhitov R. Recognition of microorganisms and activation of the immune response. Nature. 2007;449:819–826. Martin GS. Sepsis, severe sepsis and septic shock: changes in incidence, pathogens and outcomes. Expert Rev Anti Infect Ther. 2012;10:701–706. Hall MJ, Williams SN, DeFrances CJ, Golosinskiy A. Inpatient care for septicemia or sepsis: a challenge for patients and hospitals. NCHS Data Brief. 2011;62:1–8. Lagu T, Rothberg MB, Shieh MS, Pekow PS, Steingrub JS, Lindenauer PK. Hospitalizations, costs, and outcomes of severe sepsis in the United States 2003 to 2007. Crit Care Med. 2012;40:754–761. Stevenson EK, Rubenstein AR, Radin GT, Wiener RS, Walkey AJ. Two decades of mortality trends among patients with severe sepsis: a comparative meta-analysis. Crit Care Med. 2014;42:625–631. Wang HE, Donnelly JP, Shapiro NI Hohmann SF, Levitan EB: Hospital variations in severe sepsis mortality. Am J Med Qual 2014, May 9. [Epub ahead of print]. Gaieski DF, Edwards JM, Kallan MJ, Carr BG. Benchmarking the incidence and mortality of severe sepsis in the United States. Crit Care Med. 2013;41:1167–1174. Manns BJ, Lee H, Doig CJ, Johnson D, Donaldson C. An economic evaluation of activated protein C treatment for severe sepsis. N Engl J Med. 2002;347:993–1000. Angus DC, Linde-Zwirbler WT, Lidicker J, Clermont G, Carcillo J, Pinksy MR. Epidemiology of severe sepsis in the United States: analysis of incidence, outcome and associated costs of care. Crit Care Med. 2001;29:1303–1310. Martin GS, Mannino DM, Eaton S, Moss M. The epidemiology of sepsis in the United States from 1979 through 2000. N Engl J Med. 2003;348:1546–1554. Vincent JL, Sakr Y, Sprung CL, Ranieri VM, Reinhart K, Gerlach H, et al. Sepsis Occurrence in Acutely III Patients Investigators: Sepsis in European intensive care units: Results of the SOAP study. Crit Care Med. 2006;34:344–353. Vincent JL, Rello J, Marshall J, Silva E, Anzueto A, Martin CD, et al. EPIC II Group of Investigators: International study of the prevalence and outcomes of infection in intensive care units. JAMA. 2009;302:2323–2329. Friedman G, Silva E, Vincent JL. Has the mortality of septic shock changed with time. Crit Care Med. 1998;26:2078–2086. Thomas L. Germs. N Engl J Med. 1972;287:553–555. Biron CA. More things in heaven and earth: defining innate and adaptive immunity. Nat Immunol. 2010;11:1080–1082. Ishii KJ, Koyama S, Nakagawa A, Coban C, Akira S. Host innate immune receptors and beyond: making sense of microbial infections. Cell Host Microbe. 2008;3:352–363. Akira S, Uematsu S, Takeuchi O. Pathogen recognition and innate immunity. Cell. 2006;124:783–801. Bianchi ME. DAMPs, PAMPs and alarmins: all we need to know about danger. J Leukoc Biol. 2007;81:1–5. Matzinger P. The danger model: a renewed sense of self. Science. 2002;296:301–305. Brodsky IE, Medzhitov R. Targeting of immune signalling networks by bacterial pathogens. Nat Cell Biol. 2009;11:521–526. West MA, Heagy W. Endotoxin tolerance: a review. Crit Care Med. 2002;30:S64–S73. Raupach B, Kaufmann SH. Immune responses to intracellular bacteria. Curr Opin Immunol. 2001;13:417–428. Weiser JN, Nahm MH. Immunity to extracellular bacteria. In: Paul WE, editor. Fundamental Immunology. 6th ed. Philadelphia: Wolters Kluwer Health/Lippincott Williams & Wilkins; 2008. p. 1182–1203. Meylan E, Tschopp J, Karin M. Intracellular pattern recognition receptors in the host response. Nature. 2006;442:39–44. Núñez G. Intracellular sensors of microbes and danger. Immunol Rev. 2011;243:5–8. Kopp E, Medzhitov R. Recognition of microbial infection by Toll-like receptors. Curr Opin Immunol. 2003;15:396–401. Kanneganti TD, Lamkanfi M, Núñez G. Intracellular NOD-like receptors in host defense and disease. Immunity. 2007;27:549–559. Modlin RL, Brightbill HD, Godowski PJ. The toll of innate immunity on microbial pathogens. N Engl J Med. 1999;340:1834–1835. Chen G, Shaw MH, Kim YG, Nunez G. NOD-like receptors: role in innate immunity and inflammatory disease. Annu Rev Pathol. 2009;4:365–398. Barton GM, Kagan JC. A cell biological view of Toll-like receptor function: regulation through compartmentalization. Nat Rev Immunol. 2009;9:535–542. Belvin MP, Anderson KV. A conserved signaling pathway: the Drosophila toll-dorsal pathway. Annu Rev Cell Dev Biol. 1996;12:393–416. Janeway CA, Medzhitov R. Lipoproteins take their toll on the host. Curr Biol. 1999;9:R879–R882. Beutler BA. TLRs and innate immunity. Blood. 2009;113:1399–1407. Janeway Jr CA, Medzhitov R. Innate immune recognition. Annu Rev Immunol. 2002;20:197–216. Brightbill HD, Modlin RL. Toll-like receptors: molecular mechanisms of the mammalian immune response. Immunology. 2000;101:1–10. Hoshino K, Takeuchi O, Kawai T, Sanjo H, Ogawa T, Takeda Y, et al. Cutting edge: Toll-like receptor 4 (TLR4)-deficient mice are hyporesponsive to lipopolysaccharide: evidence for TLR4 as the Lps gene product. J Immunol. 1999;162:3749–3752. Andonegui G, Zhou H, Bullard D, Kelly MM, Mullaly SC, McDonald B, et al. Mice that exclusively express TLR4 on endothelial cells can efficiently clear a lethal systemic Gram-negative bacterial infection. J Clin Invest. 2009;119:1921–1930. Smirnova I, Mann N, Dols A, Derkx HH, Hibberd ML, Levin M, et al. Assay of locus-specific genetic load implicates rare Toll-like receptor 4 mutations in meningococcal susceptibility. Proc Natl Acad Sci U S A. 2003;100:6075–6080. Sampath V, Mulrooney NP, Garland JS, He J, Patel AL, Cohen JD, et al. Toll-like receptor genetic variants are associated with gram-negative infections in VLBW infants. J Perinatol. 2013;33:772–777. Aliprantis AO, Yang RB, Mark MR, Suggett S, Devaux B, Radolf JD, et al. Cell activation and apoptosis by bacterial lipoproteins through toll-like receptor-2. Science. 1999;285:736–739. Schwandner R, Dziarski R, Wesche H, Rothe M, Kirschning CJ. Peptidoglycan-and lipoteichoic acid-induced cell activation is mediated by toll-like receptor 2. J Biol Chem. 1999;274:17406–17409. Aderem A, Ulevitch RJ. Toll-like receptors in the induction of the innate immune response. Nature. 2000;406:782–787. Takeuchi O, Hoshino K, Akira S. Cutting edge: TLR2-deficient and MyD88-deficient mice are highly susceptible to Staphylococcus aureus infection. J Immunol. 2000;165:5392–5396. Tian J, Avalos AM, Mao SY, Chen B, Senthil K, Wu H, et al. Toll-like receptor 9-dependent activation by DNA-containing immune complexes is mediated by HMGB1 and RAGE. Nat Immunol. 2007;8:487–496. O’Neill LAJ, Golenbock D, Bowie AG. The history of Toll-like receptors: redefining innate immunity. Nat Rev Immunol. 2013;13:453–460. Takeda K, Akira S. TLR signaling pathways. Semin Immunol. 2004;16:3–9. Kawai T, Akira S. TLR signalling. Cell Death Differ. 2006;13:816–825. Yamamoto M, Sato S, Hemmi H, Hoshino K, Kaisho T, Sanjo H, et al. Role of adaptor TRIF in the MyD88-independent toll-like receptor signaling pathway. Science. 2003;301:640–643. Kawai T, Akira S. The role of pattern-recognition receptors in innate immunity: update on toll-like receptors. Nat Immunol. 2010;11:373–384. Shaw MH, Reimer T, Kim YG. NOD-like receptors (NLRs): bona fide intracellular microbial sensors. Curr Opin Immunol. 2008;20:377–382. Inohara N, Chamaillard M, McDonald C, Nunez G. NOD-LRR proteins: role in host-microbial interactions and inflammatory disease. Annu Rev Biochem. 2005;74:355–383. Ting JP, Davis BK. CATERPILLER: a novel gene family important in immunity, cell death, and diseases. Annu Rev Immunol. 2005;23:387–414. Fukata M, Vamadevan AS, Abreu MT. Toll-like receptors (TLRs) and Nod-like receptors (NLRs) in inflammatory disorders. Semin Immunol. 2009;21:242–253. Fritz JH, Ferrero RL, Philpott DJ, Girardin SE. Nod-like proteins in immunity, inflammation and disease. Nat Immunol. 2006;7:1250–1257. Ting JP, Lovering RC, Alnemri ES, Bertin J, Boss JM, Davis BK, et al. The NLR gene family: a standard nomenclature. Immunity. 2008;28:285–287. Proell M, Riedl SJ, Fritz JH, Rojas AM, Schwarzenbacher R. The Nod-like receptor (NLR) family: a tale of similarities and differences. PLoS One. 2008;3:e2119. Chamaillard M, Hashimoto M, Horie Y, Masumoto J, Qiu S, Saab L, et al. An essential role for NOD1 in host recognition of bacterial peptidoglycan containing diaminopimelic acid. Nat Immunol. 2003;4:702–707. Girardin SE, Boneca IG, Carneiro LA, Antignac A, Jéhanno M, Viala J, et al. Nod1 detects a unique muropeptide from gram-negative bacterial peptidoglycan. Science. 2003;300:1584–1587. Inohara N, Ogura Y, Fontalba A, Gutierrez O, Pons F, Crespo J, et al. Host recognition of bacterial muramyl dipeptide mediated through NOD2. Implications for Crohn’s disease. J Biol Chem. 2003;278:5509–5512. Girardin SE, Travassos LH, Hervé M, Blanot D, Boneca IG, Philpott DJ, et al. Nod2 is a general sensor of peptidoglycan through muramyl dipeptide (MDP) detection. J Biol Chem. 2003;278:8869–8872. Inohara N, Koseki T, del Peso L, Hu Y, Yee C, Chen S, et al. Nod1, an Apaf-1-like activator of caspase-9 and nuclear factor-kappaB. J Biol Chem. 1999;274:14560–14567. Gutierrez O, Pipaon C, Inohara N, Fontalba A, Ogura Y, Prosper F, et al. Induction of Nod2 in myelomonocytic and intestinal epithelial cells via nuclear factor-kappa B activation. J Biol Chem. 2002;277:41701–41705. Hasegawa M, Fujimoto Y, Lucas PC, Nakano H, Fukase K, Nuñez G, et al. A critical role of RICK/RIP2 polyubiquitination in Nod-induced NF-kappaB activation. EMBO J. 2008;27:373–383. Girardin SE, Tournebize R, Mavris M, Page AL, Li X, Stark GR, et al. CARD4/Nod1 mediates NF-κB and JNK activation by invasive Shigella flexneri. EMBO Rep. 2001;2:736–742. Opitz B, Püschel A, Schmeck B, Hocke AC, Rosseau S, Hammerschmidt S, et al. Nucleotide-binding oligomerization domain proteins are innate immune receptors for internalized Streptococcus pneumoniae. J Biol Chem. 2004;279:36426–36432. Ferrand J, Ferrero RL. Recognition of extracellular bacteria by NLRs and its role in the development of adaptive immunity. Front Immunol. 2013;4:344. Viala J, Chaput C, Boneca IG, Cardona A, Girardin SE, Moran AP, et al. Nod1 responds to peptidoglycan delivered by the Helicobacter pylori cag pathogenicity island. Nat Immunol. 2004;5:1166–1174. Hruz P, Zinkernagel AS, Jenikova G, Botwin GJ, Hugot JP, Karin M, et al. NOD2 contributes to cutaneous defense against Staphylococcus aureus through alpha-toxin-dependent innate immune activation. Proc Natl Acad Sci U S A. 2009;106:12873–12878. Shaw MH, Reimer T, Sanchez-Valdepenas C, Warner N, Kim YG, Fresno M, et al. T cell-intrinsic role of Nod2 in promoting type 1 immunity to Toxoplasma gondii. Nat Immunol. 2009;10:1267–1274. Ogura Y, Bonen DK, Inohara N, Nicolae DL, Chen FF, Ramos R, et al. A frameshift mutation in NOD2 associated with increased susceptibility to Crohn’s disease. Nature. 2001;411:603–606. Strober W, Murray PJ, Kitani A, Watanabe T. Signalling pathways and molecular interactions of NOD1 and NOD2. Nat Rev Immunol. 2006;6:9–20. Magalhaes JG, Lee J, Geddes K, Rubino S, Philpott DJ, Girardin SE. Essential role of Rip2 in the modulation of innate and adaptive immunity triggered by Nod1 and Nod2 ligands. Eur J Immunol. 2011;41:1445–1455. Chin AI, Dempsey PW, Brun K, Miller JF, Xu Y, Cheng G. Involvement of receptor-interacting protein 2 in innate and adaptive immune responses. Nature. 2002;416:190–194. Deshmukh HS, Hamburger JB, Ahn SH, McCafferty DG, Yang SR, Fowler Jr VG. Critical role of NOD2 in regulating the immune response to Staphylococcus aureus. Infect Immun. 2009;77:1376–1382. Bafica A, Santiago HC, Goldszmid R, Ropert C, Gazzinelli RT, Sher A. Cutting edge: TLR9 and TLR2 signaling together account for MyD88-dependent control of parasitemia in Trypanosoma cruzi infection. J Immunol. 2006;177:3515–3519. Albiger B, Dahlberg S, Sandgren A, Wartha F, Beiter K, Katsuragi H, et al. Toll-like receptor 9 acts at an early stage in host defence against pneumococcal infection. Cell Microbiol. 2007;9:633–644. Blander JM, Medzhitov R. Regulation of phagosome maturation by signals from toll-like receptors. Science. 2004;304:1014–1018. Fritz JH, Girardin SE, Fitting C, Werts C, Mengin-Lecreulx D, Caroff M, et al. Synergistic stimulation of human monocytes and dendritic cells by Toll-like receptor 4 and NOD1- and NOD2-activating agonists. Eur J Immunol. 2005;35:2459–2470. Meylan E, Tschopp J. The RIP kinases: crucial integrators of cellular stress. Trends Biochem Sci. 2005;30:151–159. Shimada K, Chen S, Dempsey PW, Sorrentino R, Alsabeh R, Slepenkin AV, et al. The NOD/RIP2 pathway is essential for host defenses against Chlamydophila pneumoniae lung infection. PLoS Pathog. 2009;5:e1000379. Philpott DJ, Girardin SE. The role of Toll-like receptors and Nod proteins in bacterial infection. Mol Immunol. 2004;41:1099–1108. Kobayashi KS, Chamaillard M, Ogura Y, Henegariu O, Inohara N, Nunez G, et al. Nod2-dependent regulation of innate and adaptive immunity in the intestinal tract. Science. 2005;307:731–734. Traub S, Kubasch N, Morath S, Kresse M, Hartung T, Schmidt RR, et al. Structural requirements of synthetic muropeptides to synergize with lipopolysaccharide in cytokine induction. J Biol Chem. 2004;279:8694–8700. Schwarz H, Posselt G, Wurm P, Ulbing M, Duschl A, Horejs-Hoeck J. TLR8 and NOD signaling synergistically induce the production of IL-1β and IL-23 in monocyte-derived DCs and enhance the expression of the feedback inhibitor SOCS2. Immunobiology. 2013;218:533–542. Takada H, Yokoyama S, Yang S. Enhancement of endotoxin activity by muramyldipeptide. J Endotoxin Res. 2002;8:337–342. Chen CM, Gong Y, Zhang M, Chen JJ. Reciprocal cross-talk between Nod2 and TAK1 signaling pathways. J Biol Chem. 2004;279:25876–25882. Tsai WH, Huang DY, Yu YH, Chen CY, Lin WW. Dual roles of NOD2 in TLR4-mediated signal transduction and–induced inflammatory gene expression in macrophages. Cell Microbiol. 2011;13:717–730. Davis BK, Wen H, Ting JPY. The inflammasome NLRs in immunity, inflammation, and associated diseases. Annu Rev Immunol. 2011;29:707–735. Kim YG, Park JH, Shaw MH, Franchi L, Inohara N, Núñez G. The cytosolic sensors Nod1 and Nod2 are critical for bacterial recognition and host defense after exposure to Toll-like receptor ligands. Immunity. 2008;28:246–257. Lee KH, Biswas A, Liu YJ, Kobayashi KS. Proteasomal degradation of Nod2 protein mediates tolerance to bacterial cell wall components. J Biol Chem. 2012;287:39800–39811. Magalhaes JG, Fritz JH, Le Bourhis L, Sellge G, Travassos LH, Selvanantham T, et al. Nod2-dependent Th2 polarization of antigen-specific immunity. J Immunol. 2008;181:7925–7935. Lamkanfi M, Sarkar A, Vande Walle L, Vitari AC, Amer AO, Wewers MD, et al. Inflammasome-dependent release of the alarmin HMGB1 in endotoxemia. J Immunol. 2010;185:4385–4392. Suda K, Kitagawa Y, Ozawa S, Saikawa Y, Ueda M, Ebina M, et al. Anti-high mobility group box chromosomal protein 1 antibodies improve survival of rats with sepsis. World J Surg. 2006;30:1755–1762. Opal SM, Laterre PF, Francois B, LaRosa SP, Angus DC, Mira JP, et al. Effect of eritoran, an antagonist of MD2-TLR4, on mortality in patients with severe sepsis: the ACCESS randomized trial. JAMA. 2013;309:1154–6210. Roger T, Froidevaux C, Le Roy D, Reymond MK, Chanson AL, Mauri D, et al. Protection from lethal gram-negative bacterial sepsis by targeting Toll-like receptor 4. Proc Natl Acad Sci U S A. 2009;106:2348–2352. Daubeuf B, Mathison J, Spiller S, Hugues S, Herren S, Ferlin W, et al. TLR4/MD2 monoclonal antibody therapy affords protection in experimental models of septic shock. J Immunol. 2007;179:6107–6114. van Lieshout MH, van der Poll T, Van’t Veer C. TLR4 inhibition impairs bacterial clearance in a therapeutic setting in murine abdominal sepsis. Inflamm Res. 2014;63:927–933. Kissner TL, Moisan L, Mann E, Alam S, Ruthel G, Ulrich RG, et al. A small molecule that mimics the BB-loop in the Toll/IL-1 receptor domain of MyD88 attenuates staphylococcal enterotoxin B-induced pro-inflammatory cytokine production and toxicity in mice. J Biol Chem. 2011;286:31385–31390. Juliana C, Fernandes-Alnemri T, Wu J, Datta P, Solorzano L, Yu JW, et al. Anti-inflammatory compounds parthenolide and Bay 11–7082 are direct inhibitors of the inflammasome. J Biol Chem. 2010;285:9792–9802. 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;79:34–41. Takashima K, Matsunaga N, Yoshimatsu M, Hazeki K, Kaisho T, Uekata M, et al. Analysis of binding site for the novel small- molecule TLR4 signal transduction inhibitor TAK-242 and its therapeutic effect on mouse sepsis model. Br J Pharmacol. 2009;157:1250–1262. 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;571:231–239. Sha T, Iizawa Y, Ii M. Combination of Imipenem and Tak-242, a Toll-like receptor 4 signal transduction inhibitor, improves survival in a murine model of polymicrobial sepsis. Shock. 2011;35:205–209. Takeda [http://www.takeda.com/news/2009/20090220_3678.html] Rice T, Wheeler A, Bernard G, Vincent JL, Angus D, Aikawa N, et al. A randomized, double-blind, placebo-controlled trial of TAK-242 for the treatment of severe sepsis. Crit Care Med. 2010;38:1685–1694. Meng G, Rutz M, Schiemann M, Metzger J, Grabiec A, Schwandner R, et al. Antagonistic antibody prevents Toll-like receptor 2-driven lethal shock-like syndromes. J Clin Invest. 2004;113:1473–1481. Spiller S, Elson G, Ferstl R, Dreher S, Mueller T, Freudenberg M, et al. TLR4-induced IFN-gamma production increases TLR2 sensitivity and drives gram-negative sepsis in mice. J Exp Med. 2008;205:1747–1754. Cavassani KA, Ishii M, Wen H, Schaller MA, Lincoln PM, Lukacs NW, et al. TLR3 is an endogenous sensor of tissue necrosis during acute inflammatory events. J Exp Med. 2008;205:2609–2621. Wardowska A, Dzierzbicka K, Szarynska M, Dabrowska-Szponar M, Wisniewska K, Mysliwski A, et al. Analogues of muramyl dipeptide (MDP) and tuftsin limit infection and inflammation in murine model of sepsis. Vaccine. 2009;27:369–374. Darcissac ECA, Vidal V, Guillaume M, Thebault JJ, Bahr GM. Clinical tolerance and profile of cytokine induction in healthy volunteers following the simultaneous administration of IFN-α and the synthetic immunomodulator murabutide. J Interferon Cytokine Res. 2001;21:655–661. Mine Y, Yokota Y, Wakai Y, Fukada S, Nishida M, Goto S, et al. Immunoactive peptides, FK-156 and FK-565. I. Enhancement of host resistance to microbial infection in mice. J Antibiot. 1983;36:1045–1050. Hackam DJ, Gribar SC: Use of toll-like receptor-9 agonists, toll-like receptor-4 antagonists, and/or nuclear oligomerization domain-2 agonists for the treatment or prevention of toll-like receptor-4-associated disorders. US Patent No. 8188058. 29 May 2012. Theofilopoulos AN, Baccala R, Beutler B, Kono DH. Type I interferons (α/β) in immunity and autoimmunity. Annu Rev Immunol. 2005;23:307–335. Utaisincharoen P, Kespichayawattana W, Anuntagool N, Chaisuriya P, Pichyangkul S, Krieg AM, et al. CpG ODN enhances uptake of bacteria by mouse macrophages. Clin Exp Immunol. 2003;132:70–75. Ribes S, Ebert S, Regen T, Agarwal A, Tauber SC, Czesnik D, et al. Toll-like receptor stimulation enhances phagocytosis and intracellular killing of nonencapsulated and encapsulated Streptococcus pneumoniae by murine microglia. Infect Immun. 2010;78:865–871. Fink MP. Animal models of sepsis. Virulence. 2014;5:143–153.