Role of Toll-like receptors, NOD-like receptors and RIG-I-like receptors in endothelial cells and systemic infections

Summary

Bacteraemia and viraemia are characterised by pathogens entering the bloodstream. Endothelial cells are among the first cells coming into contact with the microbes and also some endogenous molecules which are released by tissue damage. As part of the innate immune system, endothelial cells respond to these contacts by producing inflammatory mediators and expressing surface molecules. The initial sensing of microbial and endogenous danger-associated molecules is mediated by so-called pattern recognition receptors (PRRs). PRRs can be classified in different protein families such as the Toll-like receptors, the NODlike receptors and the RIG-I-like receptors. By activating inflammatory gene transcription and posttranslational processing, PRRs control the immediate innate immune reaction and also the subsequent adaptive immune response. Here we describe the current knowledge of extra-and intracellular PRRs in endothelial cells and their potential role in sepsis and vascular diseases.

Keywords

Toll-like receptor - NOD-like receptors - RIG-I-like receptor - endothelial cells

• References

• 1 Pober JS, Sessa WC. Evolving functions of endothelial cells in inflammation. Nat Rev Immunol 2007; 07: 803-815.
• 2 Schouten M, Wiersinga WJ, Levi M. et al. Inflammation, endothelium, and coagulation in sepsis. J Leukoc Biol 2008; 83: 536-545.
• 3 Vandenbroucke E, Mehta D, Minshall R. et al. Regulation of endothelial junctional permeability. Ann N Y Acad Sci 2008; 1123: 134-145.
• 4 Opitz B, Hippenstiel S, Eitel J. et al. Extra-and intracellular innate immune recognition in endothelial cells. Thromb Haemost 2007; 98: 319-326.
• 5 Rittirsch D, Flierl MA, Ward PA. Harmful molecular mechanisms in sepsis. Nat Rev Immunol 2008; 08: 776-787.
• 6 Beutler BA TLRs and innate immunity. Blood. 2009 113. 1399-1407.
• 7 Chen G, Shaw MH, Kim YG. et al. Nod-like Receptors: Role in Innate Immunity and Inflammatory Disease. Annu Rev Pathol 2009; 04: 365-398.
• 8 Fritz JH, Ferrero RL, Philpott DJ. et al. Nod-like proteins in immunity, inflammation and disease. Nat Immunol 2006; 07: 1250-1257.
• 9 Ting JP, Willingham SB, Bergstralh DT. NLRs at the intersection of cell death and immunity. Nat Rev Immunol 2008; 08: 372-379.
• 10 Yoneyama M, Fujita T. RNA recognition and signal transduction by RIG-I-like receptors. Immunol Rev 2009; 227: 54-65.
• 11 Aliprantis AO, Yang RB, Mark MR. et al. Cell activation and apoptosis by bacterial lipoproteins through toll-like receptor-2. Science 1999; 285: 736-739.
• 12 Opitz B, Schroder NW, Spreitzer I. et al. Toll-like receptor-2 mediates Treponema glycolipid and lipoteichoic acid-induced NF-kappaB translocation. J Biol Chem 2001; 276: 22041-22047.
• 13 Schwandner R, Dziarski R, Wesche H. et al. Peptidoglycan-and lipoteichoic acid-induced cell activation is mediated by toll-like receptor 2. J Biol Chem 1999; 274: 17406-17409.
• 14 Takeuchi O, Kawai T, Muhlradt PF. et al. Discrimination of bacterial lipoproteins by Toll-like receptor 6. Int Immunol 2001; 13: 933-940.
• 15 Takeuchi O, Sato S, Horiuchi T. et al. Cutting edge: role of Toll-like receptor 1 in mediating immune response to microbial lipoproteins. J Immunol 2002; 169: 10-14.
• 16 Underhill DM, Ozinsky A, Hajjar AM. et al. The Toll-like receptor 2 is recruited to macrophage phagosomes and discriminates between pathogens. Nature 1999; 401: 811-815.
• 17 Alexopoulou L, Holt AC, Medzhitov R. et al. Recognition of double-stranded RNA and activation of NF-kappaB by Toll-like receptor 3. Nature 2001; 413: 732-738.
• 18 Heil F, Hemmi H, Hochrein H. et al. Species-specific recognition of single-stranded RNA via toll-like receptor 7 and 8. Science 2004; 303: 1526-1529.
• 19 Akira S, Uematsu S, Takeuchi O. Pathogen recognition and innate immunity. Cell 2006; 124: 783-801.
• 20 Miller YI, Viriyakosol S, Worrall DS. et al. Toll-like receptor 4-dependent and -independent cytokine secretion induced by minimally oxidized low-density lipoprotein in macrophages. Arterioscler Thromb Vasc Biol 2005; 25: 1213-1219.
• 21 Poltorak A, He X, Smirnova I. et al. Defective LPS signaling in C3H/HeJ and C57BL/10ScCr mice: mutations in Tlr4 gene. Science 1998; 282: 2085-2088.
• 22 Hayashi F, Smith KD, Ozinsky A. et al. The innate immune response to bacterial flagellin is mediated by Toll-like receptor 5. Nature 2001; 410: 1099-1103.
• 23 Hemmi H, Takeuchi O, Kawai T. et al. A Toll-like receptor recognizes bacterial DNA. Nature 2000; 408: 740-745.
• 24 Kawai T, Akira S. The roles of TLRs, RLRs and NLRs in pathogen recognition. Int Immunol 2009; 21: 317-337.
• 25 O’Neill LA, Bowie AG. The family of five: TIRdomain-containing adaptors in Toll-like receptor signalling. Nat Rev Immunol 2007; 07: 353-364.
• 26 Bulut Y, Faure E, Thomas L. et al. Chlamydial heat shock protein 60 activates macrophages and endothelial cells through Toll-like receptor 4 and MD2 in a MyD88-dependent pathway. J Immunol 2002; 168: 1435-1440.
• 27 Frantz S, Kobzik L, Kim YD. et al. Toll4 (TLR4) expression in cardiac myocytes in normal and failing myocardium. J Clin Invest 1999; 104: 271-280.
• 28 Li J, Ma Z, Tang ZL. et al. CpG DNA-mediated immune response in pulmonary endothelial cells. Am J Physiol Lung Cell Mol Physiol 2004; 287: L552-L558.
• 29 Loos T, Dekeyzer L, Struyf S. et al. TLR ligands and cytokines induce CXCR3 ligands in endothelial cells: enhanced CXCL9 in autoimmune arthritis. Lab Invest 2006; 86: 902-916.
• 30 Maaser C, Heidemann J, von Eiff C. et al. Human intestinal microvascular endothelial cells express Tolllike receptor 5: a binding partner for bacterial flagellin. J Immunol 2004; 172: 5056-5062.
• 31 Tissari J, Siren J, Meri S. et al. IFN-alpha enhances TLR3-mediated antiviral cytokine expression in human endothelial and epithelial cells by up-regulating TLR3 expression. J Immunol 2005; 174: 4289-4294.
• 32 Faure E, Thomas L, Xu H. et al. Bacterial lipopolysaccharide and IFN-gamma induce Toll-like receptor 2 and Toll-like receptor 4 expression in human endothelial cells: role of NF-kappa B activation. J Immunol 2001; 166: 2018-2024.
• 33 Dunzendorfer S, Lee HK Tobias PS Flow-dependent regulation of endothelial Toll-like receptor 2 expression through inhibition of SP1 activity. Circ Res 2004; 95: 684-691.
• 34 Fan J, Frey RS, Malik AB. TLR4 signaling induces TLR2 expression in endothelial cells via neutrophil NADPH oxidase. J Clin Invest 2003; 112: 1234-1243.
• 35 Harari OA, Alcaide P, Ahl D. et al. Absence of TRAM restricts Toll-like receptor 4 signaling in vascular endothelial cells to the MyD88 pathway. Circ Res 2006; 98: 1134-1140.
• 36 Dauphinee SM, Karsan A. Lipopolysaccharide signaling in endothelial cells. Lab Invest 2006; 86: 9-22.
• 37 Ye X, Ding J, Zhou X. et al. Divergent roles of endothelial NF-kappaB in multiple organ injury and bacterial clearance in mouse models of sepsis. J Exp Med 2008; 205: 1303-1315.
• 38 Andonegui G, Bonder CS, Green F. et al. Endothelium-derived Toll-like receptor-4 is the key molecule in LPS-induced neutrophil sequestration into lungs. J Clin Invest 2003; 111: 1011-1020.
• 39 Shibamiya A, Hersemeyer K, Schmidt WT. et al. A key role for Toll-like receptor-3 in disrupting the hemostasis balance on endothelial cells. Blood 2009; 113: 714-722.
• 40 Martinon F, Mayor A, Tschopp J. The inflammasomes: guardians of the body. Annu Rev Immunol 2009; 27: 229-265.
• 41 Marina-Garcia N, Franchi L, Kim YG. et al. Clathrin-and dynamin-dependent endocytic pathway regulates muramyl dipeptide internalization and NOD2 activation. J Immunol 2009; 182: 4321-4327.
• 42 Ratner AJ, Aguilar JL, Shchepetov M. et al. Nod1 mediates cytoplasmic sensing of combinations of extracellular bacteria. Cell Microbiol 2007; 09: 1343-1351.
• 43 Swaan PW, Bensman T, Bahadduri PM. et al. Bacterial peptide recognition and immune activation facilitated by human peptide transporter PEPT2. Am J Respir Cell Mol Biol 2008; 39: 536-542.
• 44 Vavricka SR, Musch MW, Chang JE. et al. hPepT1 transports muramyl dipeptide, activating NF-kappaB and stimulating IL-8 secretion in human colonic Caco2/bbe cells. Gastroenterology 2004; 127: 1401-1409.
• 45 Viala J, Chaput C, Boneca IG. et al. Nod1 responds to peptidoglycan delivered by the Helicobacter pylori cag pathogenicity island. Nat Immunol 2004; 05: 1166-1174.
• 46 Chamaillard M, Hashimoto M, Horie Y. et al. An essential role for NOD1 in host recognition of bacterial peptidoglycan containing diaminopimelic acid. Nat Immunol 2003; 04: 702-707.
• 47 Girardin SE, Boneca IG, Carneiro LA. et al. Nod1 detects a unique muropeptide from gram-negative bacterial peptidoglycan. Science 2003; 300: 1584-1587.
• 48 Girardin SE, Boneca IG, Viala J. et al. Nod2 is a general sensor of peptidoglycan through muramyl dipeptide (MDP) detection. J Biol Chem 2003; 278: 8869-8872.
• 49 Inohara N, Ogura Y, Fontalba A. et al. Host recognition of bacterial muramyl dipeptide mediated through NOD2. Implications for Crohn’s disease. J Biol Chem 2003; 278: 5509-5512.
• 50 Chin AI, Dempsey PW, Bruhn K. et al. Involvement of receptor-interacting protein 2 in innate and adaptive immune responses. Nature 2002; 416: 190-194.
• 51 Kobayashi K, Inohara N, Hernandez LD. et al. RICK/Rip2/CARDIAK mediates signalling for receptors of the innate and adaptive immune systems. Nature 2002; 416: 194-199.
• 52 Hsu YM, Zhang Y, You Y. et al. The adaptor protein CARD9 is required for innate immune responses to intracellular pathogens. Nat Immunol 2007; 08: 198-205.
• 53 Barnich N, Aguirre JE, Reinecker HC. et al. Membrane recruitment of NOD2 in intestinal epithelial cells is essential for nuclear factor-{kappa}B activation in muramyl dipeptide recognition. J Cell Biol 2005; 170: 21-26.
• 54 Eitel J, Krull M, Hocke AC. et al. Beta-PIX and Rac1 GTPase mediate trafficking and negative regulation of NOD2. J Immunol 2008; 181: 2664-2671.
• 55 Kufer TA, Kremmer E, Adam AC. et al. The pattern-recognition molecule Nod1 is localized at the plasma membrane at sites of bacterial interaction. Cell Microbiol 2008; 10: 477-486.
• 56 Legrand-Poels S, Kustermans G, Bex F. et al. Modulation of Nod2-dependent NF-kappaB signaling by the actin cytoskeleton. J Cell Sci 2007; 120: 1299-1310.
• 57 Opitz B, Forster S, Hocke AC. et al. Nod1-mediated endothelial cell activation by Chlamydophila pneumoniae. Circ Res 2005; 96: 319-326.
• 58 Opitz B, Puschel A, Beermann W. et al. Listeria monocytogenes activated p38 MAPK and induced IL-8 secretion in a nucleotide-binding oligomerization domain 1-dependent manner in endothelial cells. J Immunol 2006; 176: 484-490.
• 59 Davey MP, Martin TM, Planck SR. et al. Human endothelial cells express NOD2/CARD15 and increase IL-6 secretion in response to muramyl dipeptide. Microvasc Res 2006; 71: 103-107.
• 60 Oh HM, Lee HJ, Seo GS. et al. Induction and localization of NOD2 protein in human endothelial cells. Cell Immunol 2005; 237: 37-44.
• 61 Mosa A, Trumstedt C, Eriksson E. et al. Non-hematopoietic cells control the outcome of infection with Listeria monocytogenes in a NOD1-dependent manner. Infect Immun 2009; 77: 2908-2918.
• 62 Shimada K, Chen S, Dempsey PW. et al. The NOD/ RIP2 pathway is essential for host defenses against Chlamydophila pneumoniae lung infection. PLoS Pathog 2009; 05: e1000379.
• 63 Geddes BJ, Wang L, Huang WJ. et al. Human CARD12 is a novel CED4/Apaf-1 family member that induces apoptosis. Biochem Biophys Res Commun 2001; 284: 77-82.
• 64 Franchi L, Amer A, Body-Malapel M. et al. Cytosolic flagellin requires Ipaf for activation of caspase-1 and interleukin 1beta in salmonella-infected macrophages. Nat Immunol 2006; 07: 576-582.
• 65 Lightfield KL, Persson J, Brubaker SW. et al. Critical function for Naip5 in inflammasome activation by a conserved carboxy-terminal domain of flagellin. Nat Immunol 2008; 09: 1171-1178.
• 66 Miao EA, Alpuche-Aranda CM, Dors M. et al. Cytoplasmic flagellin activates caspase-1 and secretion of interleukin 1beta via Ipaf. Nat Immunol 2006; 07: 569-575.
• 67 Suzuki T, Franchi L, Toma C, et al Differential regulation of caspase-1 activation, pyroptosis, and autophagy via Ipaf and ASC in Shigella-infected macrophages. PLoS Pathog 2007; 03: e111.
• 68 Vinzing M, Eitel J, Lippmann J. et al. NAIP and Ipaf control Legionella pneumophila replication in human cells. J Immunol 2008; 180: 6808-6815.
• 69 Zamboni DS, Kobayashi KS, Kohlsdorf T. et al. The Birc1e cytosolic pattern-recognition receptor contributes to the detection and control of Legionella pneumophila infection. Nat Immunol 2006; 07: 318-325.
• 70 Rolain JM, Novelli S, Ventosilla P. et al. Immunofluorescence detection of Bartonella bacilliformis flagella in vitro and in vivo in human red blood cells as viewed by laser confocal microscopy. Ann N Y Acad Sci 2003; 990: 581-584.
• 71 Shen A, Higgins DE. The MogR transcriptional repressor regulates nonhierarchal expression of flagellar motility genes and virulence in Listeria monocytogenes. PLoS Pathog 2006; 02: e30.
• 72 Agostini L, Martinon F, Burns K. et al. NALP3 forms an IL-1beta-processing inflammasome with increased activity in Muckle-Wells autoinflammatory disorder. Immunity 2004; 20: 319-325.
• 73 Fink SL, Bergsbaken T, Cookson BT. Anthrax lethal toxin and Salmonella elicit the common cell death pathway of caspase-1-dependent pyroptosis via distinct mechanisms. Proc Natl Acad Sci USA 2008; 105: 4312-4317.
• 74 Martinon F, Burns K, Tschopp J. The inflammasome: a molecular platform triggering activation of inflammatory caspases and processing of proIL-beta. Mol Cell 2002; 10: 417-426.
• 75 Willingham SB, Bergstralh DT, O’Connor W. et al. Microbial pathogen-induced necrotic cell death mediated by the inflammasome components CIAS1/cryopyrin/NLRP3 and ASC. Cell Host Microbe 2007; 02: 147-159.
• 76 Hsu LC, Ali SR, McGillivray S. et al. A NOD2-NALP1 complex mediates caspase-1-dependent IL-1beta secretion in response to Bacillus anthracis infection and muramyl dipeptide. Proc Natl Acad Sci USA 2008; 105: 7803-7808.
• 77 Boyden ED, Dietrich WF. Nalp1b controls mouse macrophage susceptibility to anthrax lethal toxin. Nat Genet 2006; 38: 240-244.
• 78 Eisenbarth SC, Colegio OR, O’Connor W. et al. Crucial role for the Nalp3 inflammasome in the immunostimulatory properties of aluminium adjuvants. Nature 2008; 453: 1122-1126.
• 79 Halle A, Hornung V, Petzold GC. et al. The NALP3 inflammasome is involved in the innate immune response to amyloid-beta. Nat Immunol 2008; 09: 857-865.
• 80 Hornung V, Bauernfeind F, Halle A. et al. Silica crystals and aluminum salts activate the NALP3 inflammasome through phagosomal destabilization. Nat Immunol 2008; 09: 847-856.
• 81 Kanneganti TD, Ozoren N, Body-Malapel M. et al. Bacterial RNA and small antiviral compounds activate caspase-1 through cryopyrin/Nalp3. Nature 2006; 440: 233-236.
• 82 Mariathasan S, Weiss DS, Newton K. et al. Cryopyrin activates the inflammasome in response to toxins and ATP. Nature 2006; 440: 228-232.
• 83 Martinon F, Agostini L, Meylan E. et al. Identification of bacterial muramyl dipeptide as activator of the NALP3/cryopyrin inflammasome. Curr Biol 2004; 14: 1929-1934.
• 84 Martinon F, Petrilli V, Mayor A. et al. Gout-associated uric acid crystals activate the NALP3 inflammasome. Nature 2006; 440: 237-241.
• 85 Sutterwala FS, Ogura Y, Szczepanik M. et al. Critical role for NALP3/CIAS1/Cryopyrin in innate and adaptive immunity through its regulation of caspase-1. Immunity 2006; 24: 317-327.
• 86 Yamasaki K, Muto J, Taylor KR. et al. NLRP3/cryopyrin is necessary for IL-1beta release in response to hyaluronan, an endogenous trigger of inflammation in response to injury. J Biol Chem 2009; 284: 12762-12771.
• 87 Sarkar A, Hall MW, Exline M. et al. Caspase-1 regulates Escherichia coli sepsis and splenic B cell apoptosis independently of interleukin-1beta and interleukin-18. Am J Respir Crit Care Med 2006; 174: 1003-1010.
• 88 Mariathasan S, Newton K, Monack DM. et al. Differential activation of the inflammasome by caspase-1 adaptors ASC and Ipaf. Nature 2004; 430: 213-218.
• 89 Saleh M, Mathison JC, Wolinski MK. et al. Enhanced bacterial clearance and sepsis resistance in caspase-12-deficient mice. Nature 2006; 440: 1064-1068.
• 90 Saleh M, Vaillancourt JP, Graham RK. et al. Differential modulation of endotoxin responsiveness by human caspase-12 polymorphisms. Nature 2004; 429: 75-79.
• 91 Fahy RJ, Exline MC, Gavrilin MA. et al. Inflammasome mRNA expression in human monocytes during early septic shock. Am J Respir Crit Care Med 2008; 177: 983-988.
• 92 Schumann RR, Belka C, Reuter D. et al. Lipopolysaccharide activates caspase-1 (interleukin-1-converting enzyme) in cultured monocytic and endothelial cells. Blood 1998; 91: 577-584.
• 93 Kuchler AM, Pollheimer J, Balogh J. et al. Nuclear interleukin-33 is generally expressed in resting endothelium but rapidly lost upon angiogenic or proinflammatory activation. Am J Pathol 2008; 173: 1229-1242.
• 94 Moussion C, Ortega N, Girard JP. The IL-1-like cytokine IL-33 is constitutively expressed in the nucleus of endothelial cells and epithelial cells in vivo: a novel ‘alarmin’?. PLoS ONE 2008; 03: e3331.
• 95 Cayrol C and Girard JP The IL-1-like cytokine IL-33 is inactivated after maturation by caspase-1. Proc Natl Acad Sci USA. 2009; 106: 9021-9026.
• 96 Miller AM, Xu D, Asquith DL. et al. IL-33 reduces the development of atherosclerosis. J Exp Med 2008; 205: 339-346.
• 97 Andrejeva J, Childs KS, Young DF. et al. The V proteins of paramyxoviruses bind the IFN-inducible RNA helicase, mda-5, and inhibit its activation of the IFNbeta promoter. Proc Natl Acad Sci USA 2004; 101: 17264-17269.
• 98 Yoneyama M, Kikuchi M, Natsukawa T. et al. The RNA helicase RIG-I has an essential function in double-stranded RNA-induced innate antiviral responses. Nat Immunol 2004; 05: 730-737.
• 99 Hornung V, Ellegast J, Kim S. et al. 5’-Triphosphate RNA is the ligand for RIG-I. Science 2006; 314: 994-997.
• 100 Kato H, Takeuchi O, Sato S. et al. Differential roles of MDA5 and RIG-I helicases in the recognition of RNA viruses. Nature 2006; 441: 101-105.
• 101 Pichlmair A, Schulz O, Tan CP. et al. RIG-I-mediated antiviral responses to single-stranded RNA bearing 5’-phosphates. Science 2006; 314: 997-1001.
• 102 Kawai T, Takahashi K, Sato S. et al. IPS-1, an adaptor triggering RIG-I-and Mda5-mediated type I interferon induction. Nat Immunol 2005; 06: 981-988.
• 103 Meylan E, Curran J, Hofmann K. et al. Cardif is an adaptor protein in the RIG-I antiviral pathway and is targeted by hepatitis C virus. Nature 2005; 437: 1167-1172.
• 104 Seth RB, Sun L, Ea CK. et al. Identification and characterization of MAVS, a mitochondrial antiviral signaling protein that activates NF-kappaB and IRF 3. Cell 2005; 122: 669-682.
• 105 Xu LG, Wang YY, Han KJ. et al. VISA is an adapter protein required for virus-triggered IFN-beta signaling. Mol Cell 2005; 19: 727-740.
• 106 Berghall H, Siren J, Sarkar D. et al. The interferoninducible RNA helicase, mda-5, is involved in measles virus-induced expression of antiviral cytokines. Microbes Infect 2006; 08: 2138-2144.
• 107 Imaizumi T, Aratani S, Nakajima T. et al. Retinoic acid-inducible gene-I is induced in endothelial cells by LPS and regulates expression of COX-2. Biochem Biophys Res Commun 2002; 292: 274-279.