Extra- and intracellular innate immune recognition in endothelial cells

Summary

The innate immune system represents the principal sensor of infections in multicellular organisms and might also mediate responses to some endogenous molecules. In this context, endothelial cells are among the first cells coming into contact with microbial or endogenous (danger-associated) molecules or whole pathogens entering the bloodstream. Since many bacteria and viruses invade the endothelium, endothelial cells are equipped with both extracellular and cytosolic surveillance systems capable of sensing microbial components, and endogenous danger-associated molecules. The receptor molecules, called pattern recognition receptors (PRRs), are classified as transmembrane or cytosolic molecules. While the transmembrane PRRs recognize extracellular and membrane-enclosed foreign organisms, the cytosolic PRRs appear to sense intracellular infections. Here we focus on both PRR classes in general, and outline the current knowledge of extra- and intracellular pattern recognition in endothelial cells and its potential role in vascular diseases and sepsis.

Keywords

Toll-like receptors - Nod-like receptors - CARD-helicases - endothelial cells

• References

• 1 Grandel U, Grimminger F. Endothelial responses to bacterial toxins in sepsis. Crit Rev Immunol 2003; 23: 267-299.
• 2 Hippenstiel S, Suttorp N. Interaction of pathogens with the endothelium. Thromb Haemost 2003; 89: 18-24.
• 3 Jaffe EA. Cell biology of endothelial cells. Hum Pathol 1987; 18: 234-239.
• 4 Janeway Jr., CA, Medzhitov R. Innate immune recognition. Annu Rev Immunol 2002; 20: 197-216.
• 5 Akira S, Uematsu S, Takeuchi O. Pathogen recognition and innate immunity. Cell 2006; 124: 783-801.
• 6 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.
• 7 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.
• 8 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.
• 9 Takeuchi O, Kawai T, Muhlradt PF. et al. Discrimination of bacterial lipoproteins by Toll-like receptor 6. Int Immunol 2001; 13: 933-940.
• 10 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.
• 11 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.
• 12 Alexopoulou L, Holt AC, Medzhitov R. et al. Recognition of double-stranded RNA and activation of NFkappaB by Toll-like receptor 3. Nature 2001; 413: 732-738.
• 13 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.
• 14 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.
• 15 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.
• 16 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.
• 17 Hemmi H, Takeuchi O, Kawai T. et al. A Toll-like receptor recognizes bacterial DNA. Nature 2000; 408: 740-745.
• 18 Lee HK, Dunzendorfer S, Soldau K. et al. Doublestranded RNA-mediated TLR3 activation is enhanced by CD14. Immunity 2006; 24: 153-163.
• 19 Wright SD, Ramos RA, Tobias PS. et al. CD14, a receptor for complexes of lipopolysaccharide (LPS) and LPS binding protein. Science 1990; 249: 1431-1433.
• 20 O’Neill LA. How Toll-like receptors signal: what we know and what we don’t know. Curr Opin Immunol 2006; 18: 3-9.
• 21 Arbibe L, Mira JP, Teusch N. et al. Toll-like receptor 2-mediated NF-kappa B activation requires a Rac1-dependent pathway. Nat Immunol 2000; 1: 533-540.
• 22 Hippenstiel S, Soeth S, Kellas B. et al. Rho proteins and the p38-MAPK pathway are important mediators for LPS-induced interleukin-8 expression in human endothelial cells. Blood 2000; 95: 3044-3051.
• 23 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.
• 24 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.
• 25 Faure E, Equils O, Sieling PA. et al. Bacterial lipopolysaccharide activates NF-kappaB through toll-like receptor 4 (TLR-4) in cultured human dermal endothelial cells. Differential expression of TLR-4 and TLR-2 in endothelial cells. J Biol Chem 2000; 275: 11058-11063.
• 26 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.
• 27 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.
• 28 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.
• 29 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.
• 30 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.
• 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 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.
• 34 Dauphinee SM, Karsan A. Lipopolysaccharide signaling in endothelial cells. Lab Invest 2006; 86: 9-22.
• 35 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.
• 36 Peters K, Unger RE, Brunner J. et al. Molecular basis of endothelial dysfunction in sepsis. Cardiovasc Res 2003; 60: 49-57.
• 37 Parry GC, Mackman N. Transcriptional regulation of tissue factor expression in human endothelial cells. Arterioscler Thromb Vasc Biol 1995; 15: 612-621.
• 38 Wu KK, Thiagarajan P. Role of endothelium in thrombosis and hemostasis. Annu Rev Med 1996; 47: 315-331.
• 39 Andonegui G, Kerfoot SM, McNagny K. et al. Platelets express functional Toll-like receptor-4. Blood 2005; 106: 2417-2423.
• 40 Aslam R, Speck ER, Kim M. et al. Platelet Toll-like receptor expression modulates lipopolysaccharide-induced thrombocytopenia and tumor necrosis factoralpha production in vivo. Blood 2006; 107: 637-641.
• 41 Rumbaut RE, Bellera RV, Randhawa JK. et al. Endotoxin enhances microvascular thrombosis in mouse cremaster venules via a TLR4-dependent, neutrophilindependent mechanism. Am J Physiol Heart Circ Physiol 2006; 290: H1671-H1679.
• 42 Ward JR, Bingle L, Judge HM. et al. Agonists of toll-like receptor (TLR)2 and TLR4 are unable to modulate platelet activation by adenosine diphosphate and platelet activating factor. Thromb Haemost 2005; 94: 831-838.
• 43 Toshchakov V, Jones BW, Perera PY. et al. TLR4, but not TLR2, mediates IFN-beta-induced STAT1alpha/beta-dependent gene expression in macrophages. Nat Immunol 2002; 3: 392-398.
• 44 Hansson GK, Libby P. The immune response in atherosclerosis: a double-edged sword. Nat Rev Immunol 2006; 6: 508-519.
• 45 Bjorkbacka H, Kunjathoor VV, Moore KJ. et al. Reduced atherosclerosis in MyD88-null mice links elevated serum cholesterol levels to activation of innate immunity signaling pathways. Nat Med 2004; 10: 416-421.
• 46 Michelsen KS, Wong MH, Shah PK. et al. Lack of Toll-like receptor 4 or myeloid differentiation factor 88 reduces atherosclerosis and alters plaque phenotype in mice deficient in apolipoprotein E. Proc Natl Acad Sci USA 2004; 101: 10679-10684.
• 47 Mullick AE, Tobias PS, Curtiss LK. Modulation of atherosclerosis in mice by Toll-like receptor 2. J Clin Invest 2005; 115: 3149-3156.
• 48 Edfeldt K, Swedenborg J, Hansson GK. et al. Expression of toll-like receptors in human atherosclerotic lesions: a possible pathway for plaque activation. Circulation 2002; 105: 1158-1161.
• 49 Kiechl S, Lorenz E, Reindl M. et al. Toll-like receptor 4 polymorphisms and atherogenesis. N Engl J Med 2002; 347: 185-192.
• 50 Michelsen KS, Doherty TM, Shah PK. et al. Role of Toll-like receptors in atherosclerosis. Circ Res 2004; 95: e96-e97.
• 51 Schroder NW, Schumann RR. Single nucleotide polymorphisms of Toll-like receptors and susceptibility to infectious disease. Lancet Infect Dis 2005; 5: 156-164.
• 52 Patrignani P, Di Febbo C, Tacconelli S. et al. Reduced thromboxane biosynthesis in carriers of toll-like receptor 4 polymorphisms in vivo. Blood 2006; 107: 3572-3574.
• 53 Sinha B, Herrmann M. Mechanism and consequences of invasion of endothelial cells by Staphylococcus aureus. Thromb Haemost 2005; 94: 266-277.
• 54 Klenk HD. Infection of the endothelium by influenza viruses. Thromb Haemost 2005; 94: 262-265.
• 55 Inohara Chamaillard, McDonald C. et al. NODLRR proteins: role in host-microbial interactions and inflammatory disease. Annu Rev Biochem 2005; 74: 355-383.
• 56 Ting JP, Davis BK. CATERPILLER: a novel gene family important in immunity, cell death, and diseases. Annu Rev Immunol 2005; 23: 387-414.
• 57 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; 4: 702-707.
• 58 Girardin SE, Boneca IG, Carneiro LA. et al. Nod1 detects a unique muropeptide from gram-negative bacterial peptidoglycan. Science 2003; 300: 1584-1587.
• 59 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.
• 60 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.
• 61 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.
• 62 Hsu YM, Zhang Y, You Y. et al. The adaptor protein CARD9 is required for innate immune responses to intracellular pathogens. Nat Immunol 2007; 8: 198-205.
• 63 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.
• 64 Oh HM, Lee HJ, Seo GS. et al. Induction and localization of NOD2 protein in human endothelial cells. Cell Immunol 2005; 237: 37-44.
• 65 Opitz B, Forster S, Hocke AC. et al. Nod1-mediated endothelial cell activation by Chlamydophila pneumoniae. Circ Res 2005; 96: 319-326.
• 66 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.
• 67 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; 7: 576-582.
• 68 Miao EA, Alpuche-Aranda CM, Dors M. et al. Cytoplasmic flagellin activates caspase-1 and secretion of interleukin 1beta via Ipaf. Nat Immunol 2006; 7: 569-575.
• 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; 7: 318-325.
• 70 Amer A, Franchi L, Kanneganti TD. et al. Regulation of Legionella Phagosome Maturation and Infection through Flagellin and Host Ipaf. J Biol Chem 2006; 281: 35217-35223.
• 71 Fortier A, de Chastellier C, Balor S. et al. Birc1e/Naip5 rapidly antagonizes modulation of phagosome maturation by Legionella pneumophila. Cell Microbiol 2007; 9: 910-923.
• 72 Peel M, Donachie W, Shaw A. Temperature-dependent expression of flagella of Listeria monocytogenes studied by electron microscopy, SDS-PAGE and western blotting. J Gen Microbiol 1988; 134: 2171-2178.
• 73 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 NY Acad Sci 2003; 990: 581-584.
• 74 Martinon F, Tschopp J. NLRs join TLRs as innate sensors of pathogens. Trends Immunol 2005; 26: 447-454.
• 75 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.
• 76 Mariathasan S, Weiss DS, Newton K. et al. Cryopyrin activates the inflammasome in response to toxins and ATP. Nature 2006; 440: 228-232.
• 77 Martinon F, Petrilli V, Mayor A. et al. Gout-associated uric acid crystals activate the NALP3 inflammasome. Nature 2006; 440: 237-241.
• 78 Boyden ED, Dietrich WF. Nalp1b controls mouse macrophage susceptibility to anthrax lethal toxin. Nat Genet 2006; 38: 240-244.
• 79 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.
• 80 Schmeck B, Beermann W, van Laak V. et al. Intracellular bacteria differentially regulated endothelial cytokine release by MAPK-dependent histone modification. J Immunol 2005; 175: 2843-2850.
• 81 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.
• 82 Yao L, Bengualid V, Lowy FD. et al. Internalization of Staphylococcus aureus by endothelial cells induces cytokine gene expression. Infect Immun 1995; 63: 1835-1839.
• 83 Carvalho D, Savage CO, Isenberg D. et al. IgG antiendothelial cell autoantibodies from patients with systemic lupus erythematosus or systemic vasculitis stimulate the release of two endothelial cell-derived mediators, which enhance adhesion molecule expression and leukocyte adhesion in an autocrine manner. Arthritis Rheum 1999; 42: 631-640.
• 84 Del Papa N, Guidali L, Sironi M. et al. Anti-endothelial cell IgG antibodies from patients with Wegener’s granulomatosis bind to human endothelial cells in vitro and induce adhesion molecule expression and cytokine secretion. Arthritis Rheum 1996; 39: 758-766.
• 85 Tedgui A, Mallat Z. Cytokines in atherosclerosis: pathogenic and regulatory pathways. Physiol Rev 2006; 86: 515-581.
• 86 Viala J, Chaput C, Boneca IG. et al. Nod1 responds to peptidoglycan delivered by the Helicobacter pylori cag pathogenicity island. Nat Immunol 2004; 5: 1166-1174.
• 87 Hugot JP, Chamaillard M, Zouali H. et al. Association of NOD2 leucine-rich repeat variants with susceptibility to Crohn’s disease. Nature 2001; 411: 599-603.
• 88 Ogura Y, Bonen DK, Inohara N. et al. A frameshift mutation in NOD2 associated with susceptibility to Crohn’s disease. Nature 2001; 411: 603-606.
• 89 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.
• 90 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; 5: 730-737.
• 91 Hornung V, Ellegast J, Kim S. et al. 5‘-Triphosphate RNA is the ligand for RIG-I. Science 2006; 314: 994-997.
• 92 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.
• 93 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.
• 94 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; 6: 981-988.
• 95 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.
• 96 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.
• 97 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.
• 98 Oganesyan G, Saha SK, Guo B. et al. Critical role of TRAF3 in the Toll-like receptor-dependent and -independent antiviral response. Nature 2006; 439: 208-211.
• 99 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.
• 100 Okabe Y, Kawane K, Akira S. et al. Toll-like receptor- independent gene induction program activated by mammalian DNA escaped from apoptotic DNA degradation. J Exp Med 2005; 202: 1333-1339.
• 101 Ishii KJ, Uematsu S, Akira S. ‘Toll’ gates for future immunotherapy. Curr Pharm Des 2006; 12: 4135-4142.