Abstract
Mammalian Toll-like receptors (TLRs) represent pattern recognition receptors of the immune system and are related to the Toll protein of Drosophila. Pathogen-associated molecular patterns (PAMPs) of microbial and viral origin bind to TLRs and initiate the innate and adaptive immune response. However, TLRs are not solely found on cells of the immune system but also on nonmyeloid cells in various tissues, e.g., on vascular cells. In addition to PAMPs, there is increasing evidence that TLRs also recognize endogenous ligands. Recent studies demonstrate the contribution of distinct TLRs in different inflammatory disorders such as cardiovascular diseases, rheumatoid arthritis, systemic lupus erythematosus, and cancer. Many of these disorders are characterized by enhanced angiogenesis which is mainly trigged by inflammation. However, this inflammation-induced angiogenesis is not only important for pathogen defense during acute infection or chronic inflammatory disorders but as well involved in regenerative processes during wound healing and tissue repair. There is cumulative evidence that TLR activation by exogenous as well as endogenous ligands especially contributes to angiogenic process in this scenario. The present chapter will summarize the current understanding of TLR-linked signal transduction in angiogenesis during inflammatory processes with future prospects for pro- or antiangiogenic therapy.
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Anderson KV, Jürgens G, Nüsslein-Volhard C (1985) Establishment of dorsal-ventral polarity in the Drosophila embryo: genetic studies on the role of the Toll gene product. Cell 42:779–789
Anderson KV, Bokla L, Nüsslein-Volhard C (1985) Establishment of dorsal-ventral polarity in the Drosophila embryo: the induction of polarity by the Toll gene product. Cell 42:791–798
Hashimoto C, Hudson KL, Anderson KV (1988) The Toll gene of Drosophila, required for dorsal-ventral embryonic polarity, appears to encode a transmembrane protein. Cell 52:269–279
Lemaitre B, Nicolas E, Michaut L et al (1996) The dorsoventral regulatory gene cassette spätzle/Toll/cactus controls the potent antifungal response in Drosophila adults. Cell 86:973–983
Valanne S, Wang JH, Rämet M (2011) The Drosophila Toll signaling pathway. J Immunol 186:649–656
Taguchi T, Mitcham JL, Dower SK et al (1996) Chromosomal localization of TIL, a gene encoding a protein related to the Drosophila transmembrane receptor Toll, to human chromosome 4p14. Genomics 32:486–488
Medzhitov R, Preston-Hurlburt P, Janeway CA Jr (1997) A human homologue of the Drosophila Toll protein signals activation of adaptive immunity. Nature 388:394–397
Poltorak A, He X, Smirnova I et al (1998) Defective LPS signaling in C3H/HeJ and C57BL/10ScCr mice: mutations in Tlr4 gene. Science 282:2085–2088
Takeda K, Kaisho T, Akira S (2003) Toll-like receptors. Annu Rev Immunol 21:335–376
Oda K, Kitano H (2006) A comprehensive map of the toll-like receptor signaling network. Mol Syst Biol 2:2006.0015
Brikos C, O’Neill LA (2008) Signalling of toll-like receptors. In: Bauer S, Hartmann G (eds) Toll-like receptors (TLRs) and innate immunity, vol 183, Handbook of experimental pharmacology. Springer, Heidelberg, pp 21–50
Brown J, Wang H, Hajishengallis GN, Martin M (2011) TLR-signaling networks: an integration of adaptor molecules, kinases, and cross-talk. J Dent Res 90:417–427
O’Neill LA, Bowie AG (2007) The family of five: TIR-domain-containing adaptors in Toll-like receptor signalling. Nat Rev Immunol 7:353–364
Hasan U, Chaffois C, Gaillard C, Saulnier V, Merck E, Tancredi S, Guiet C, Brière F, Vlach J, Lebecque S, Trinchieri G, Bates EE (2005) Human TLR10 is a functional receptor, expressed by B cells and plasmacytoid dendritic cells, which activates gene transcription through MyD88. J Immunol 174:2942–2950
Lee CC, Avalos AM, Ploegh HL (2012) Accessory molecules for Toll-like receptors and their function. Nat Rev Immunol 12:168–179
Li S, Strelow A, Fontana EJ, Wesche H (2002) IRAK-4: a novel member of the IRAK family with the properties of an IRAK-kinase. Proc Natl Acad Sci U S A 99:5567–5572
Chen ZJ (2005) Ubiquitin signalling in the NF-kappaB pathway. Nat Cell Biol 7:758–765
Sato S, Sugiyama M, Yamamoto M et al (2003) Toll/IL-1 receptor domain-containing adaptor inducing IFN-beta (TRIF) associates with TNF receptor-associated factor 6 and TANK-binding kinase 1, and activates two distinct transcription factors, NF-kappa B and IFN-regulatory factor-3, in the Toll-like receptor signaling. J Immunol 171:4304–4310
Oshiumi H, Matsumoto M, Funami K et al (2003) TICAM-1, an adaptor molecule that participates in Toll-like receptor 3-mediated interferon-beta induction. Nat Immunol 4:161–167
Honda K, Yanai H, Mizutani T 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 A101:15416–15421
Kaisho T, Akira S (2003) Regulation of dendritic cell function through toll-like receptors. Curr Mol Med 3:759–771
Satoh M, Ishikawa Y, Minami Y et al (2008) Role of Toll like receptor signaling pathway in ischemic coronary artery disease. Front Biosci 13:6708–6715
Seki E, Brenner DA (2008) Toll-like receptors and adaptor molecules in liver disease: update. Hepatology 48:322–335
Marshak-Rothstein A (2006) Toll-like receptors in systemic autoimmune disease. Nat Rev Immunol 6:823–835
Obhrai J, Goldstein DR (2006) The role of toll-like receptors in solid organ transplantation. Transplantation 81:497–502
Schmidt M, Raghavan B, Muller V et al (2010) Crucial role for human Toll-like receptor 4 in the development of contact allergy to nickel. Nat Immunol 11:814–819
Yu L, Wang L, Chen S (2010) Endogenous toll-like receptor ligands and their biological significance. J Cell Mol Med 14:2592–2603
Deiters U, Barsig J, Tawil B, Muhlradt PF (2004) The macrophage-activating lipopeptide-2 accelerates wound healing in diabetic mice. Exp Dermatol 13:731–739
Macedo L, Pinhal-Enfield G, Alshits V et al (2007) Wound healing is impaired in MyD88-deficient mice: a role for MyD88 in the regulation of wound healing by adenosine A2A receptors. Am J Pathol 171:1774–1788
Seki E, Tsutsui H, Iimuro Y et al (2005) Contribution of Toll-like receptor/myeloid differentiation factor 88 signaling to murine liver regeneration. Hepatology 41:443–450
Ribatti D (2010) The seminal work of Werner Risau in the study of the development of the vascular system. Int J Dev Biol 54:567–572
Carmeliet P (2000) Mechanisms of angiogenesis and arteriogenesis. Nat Med 6:389–395
Risau W (1997) Mechanisms of angiogenesis. Nature 386:671–674
Carmeliet P (2005) Angiogenesis in life, disease and medicine. Nature 438:932–936
Olsson AK, Dimberg A, Kreuger J, Claesson-Welsh L (2006) VEGF receptor signalling—in control of vascular function. Nat Rev Mol Cell Biol 7:359–371
Senger DR, Galli SJ, Dvorak AM et al (1983) Tumor cells secrete a vascular permeability factor that promotes accumulation of ascites fluid. Science 219:983–985
Partanen J, Armstrong E, Makela TP et al (1992) A novel endothelial cell surface receptor tyrosine kinase with extracellular epidermal growth factor homology domains. Mol Cell Biol 12:1698–1707
Augustin HG, Koh GY, Thurston G, Alitalo K (2009) Control of vascular morphogenesis and homeostasis through the angiopoietin-Tie system. Nat Rev Mol Cell Biol 10:165–177
Gridley T (2010) Notch signaling in the vasculature. Curr Top Dev Biol 92:277–309
Karamysheva AF (2008) Mechanisms of angiogenesis. Biochemistry (Mosc) 73:751–762
Bussolino F, Ziche M, Wang JM et al (1991) In vitro and in vivo activation of endothelial cells by colony-stimulating factors. J Clin Invest 87:986–995
Distler JH, Hirth A, Kurowska-Stolarska M et al (2003) Angiogenic and angiostatic factors in the molecular control of angiogenesis. Q J Nucl Med 47:149–161
Vandervelde S, van Luyn MJ, Tio RA, Harmsen MC (2005) Signaling factors in stem cell-mediated repair of infarcted myocardium. J Mol Cell Cardiol 39:363–376
Cao Y (2009) Tumor angiogenesis and molecular targets for therapy. Front Biosci 14:3962–3973
Yamaguchi Y, Yoshikawa K (2001) Cutaneous wound healing: an update. J Dermatol 28:521–534
Gharaee-Kermani M, Phan SH (2001) Role of cytokines and cytokine therapy in wound healing and fibrotic diseases. Curr Pharm Des 7:1083–1103
Frantz S, Vincent KA, Feron O, Kelly RA (2005) Innate immunity and angiogenesis. Circ Res 96:15–26
Koutroubakis IE, Tsiolakidou G, Karmiris K, Kouroumalis EA (2006) Role of angiogenesis in inflammatory bowel disease. Inflamm Bowel Dis 12:515–523
Costa C, Incio J, Soares R (2007) Angiogenesis and chronic inflammation: cause or consequence? Angiogenesis 10:149–166
Grote K, Schuett H, Schieffer B (2011) Toll-like receptors in angiogenesis. ScientificWorldJournal 11:981–991
Leibovich SJ, Chen JF, Pinhal-Enfield G et al (2002) Synergistic up-regulation of vascular endothelial growth factor expression in murine macrophages by adenosine A(2A) receptor agonists and endotoxin. Am J Pathol 160:2231–2244
Pinhal-Enfield G, Ramanathan M, Hasko G et al (2003) An angiogenic switch in macrophages involving synergy between Toll-like receptors 2, 4, 7, and 9 and adenosine A(2A) receptors. Am J Pathol 163:711–721
Hara Y, Kuroda N, Inoue K, Sato T (2009) Up-regulation of vascular endothelial growth factor expression by adenosine through adenosine A2 receptors in the rat tongue treated with endotoxin. Arch Oral Biol 54:932–942
Pollet I, Opina CJ, Zimmerman C et al (2003) Bacterial lipopolysaccharide directly induces angiogenesis through TRAF6-mediated activation of NF-kappaB and c-Jun N-terminal kinase. Blood 102:1740–1742
McCord AM, Burgess AW, Whaley MJ, Anderson BE (2005) Interaction of Bartonella henselae with endothelial cells promotes monocyte/macrophage chemoattractant protein 1 gene expression and protein production and triggers monocyte migration. Infect Immun 73:5735–5742
Rodriguez-Martinez S, Cancino-Diaz ME, Miguel PS, Cancino-Diaz JC (2006) Lipopolysaccharide from Escherichia coli induces the expression of vascular endothelial growth factor via toll-like receptor 4 in human limbal fibroblasts. Exp Eye Res 83:1373–1377
Jagavelu K, Routray C, Shergill U et al (2010) Endothelial cell toll-like receptor 4 regulates fibrosis-associated angiogenesis in the liver. Hepatology 52:590–601
McDonald DM (2001) Angiogenesis and remodeling of airway vasculature in chronic inflammation. Am J Respir Crit Care Med 164:S39–S45
Grote K, Schuett H, Salguero G et al (2010) Toll-like receptor 2/6 stimulation promotes angiogenesis via GM-CSF as a potential strategy for immune defense and tissue regeneration. Blood 115:2543–2552
Varoga D, Paulsen F, Mentlein R et al (2006) TLR-2-mediated induction of vascular endothelial growth factor (VEGF) in cartilage in septic joint disease. J Pathol 210:315–324
Cho ML, Ju JH, Kim HR et al (2007) Toll-like receptor 2 ligand mediates the upregulation of angiogenic factor, vascular endothelial growth factor and interleukin-8/CXCL8 in human rheumatoid synovial fibroblasts. Immunol Lett 108:121–128
Chang YJ, Wu MS, Lin JT, Chen CC (2005) Helicobacter pylori-induced invasion and angiogenesis of gastric cells is mediated by cyclooxygenase-2 induction through TLR2/TLR9 and promoter regulation. J Immunol 175:8242–8252
Damiano V, Caputo R, Bianco R et al (2006) Novel toll-like receptor 9 agonist induces epidermal growth factor receptor (EGFR) inhibition and synergistic antitumor activity with EGFR inhibitors. Clin Cancer Res 12:577–583
Guo Z, Chen L, Zhu Y et al (2012) Double-stranded RNA-induced TLR3 activation inhibits angiogenesis and triggers apoptosis of human hepatocellular carcinoma cells. Oncol Rep 27:396–402
Bergé M, Bonnin P, Sulpice E et al (2010) Small interfering RNAs induce target-independent inhibition of tumor growth and vasculature remodeling in a mouse model of hepatocellular carcinoma. Am J Pathol 177:3192–3201
Spaner DE, Masellis A (2007) Toll-like receptor agonists in the treatment of chronic lymphocytic leukemia. Leukemia 21:53–60
Shingu K, Kruschinski C, Lührmann A et al (2003) Intratracheal macrophage-activating lipopeptide-2 reduces metastasis in the rat lung. Am J Respir Cell Mol Biol 28:316–321
Schneider C, Schmidt T, Ziske C et al (2004) Tumour suppression induced by the macrophage activating lipopeptide MALP-2 in an ultrasound guided pancreatic carcinoma mouse model. Gut 53:355–361
Schmidt J, Welsch T, Jäger D et al (2007) Intratumoural injection of the toll-like receptor-2/6 agonist ‘macrophage-activating lipopeptide-2’ in patients with pancreatic carcinoma: a phase I/II trial. Br J Cancer 97:598–604
Cammarota R, Bertolini V, Pennesi G et al (2010) The tumor microenvironment of colorectal cancer: stromal TLR4 expression as a potential prognostic marker. J Transl Med 8:112
Kutikhin AG (2011) Association of polymorphisms in TLR genes and in genes of the Toll-like receptor signaling pathway with cancer risk. Hum Immunol 72:1095–1116
van Beijnum JR, Buurman WA, Griffioen AW (2008) Convergence and amplification of toll-like receptor (TLR) and receptor for advanced glycation end products (RAGE) signaling pathways via high mobility group B1 (HMGB1). Angiogenesis 11:91–99
Lin Q, Yang XP, Fang D et al (2011) High-mobility group box-1 mediates toll-like receptor 4-dependent angiogenesis. Arterioscler Thromb Vasc Biol 31:1024–1032
van Beijnum JR, Nowak-Sliwinska P, van den Boezem E et al (2012) Tumor angiogenesis is enforced by autocrine regulation of high-mobility group box 1. Oncogene 32:363–374
West XZ, Malinin NL, Merkulova AA et al (2010) Oxidative stress induces angiogenesis by activating TLR2 with novel endogenous ligands. Nature 467:972–976
Wang XY, Sarkar D, Fisher PB (2011) Stress-sensing toll-like receptor as a driver of angiogenesis. Pigment Cell Melanoma Res 24:7–9
Ergul A, Alhusban A, Fagan SC (2012) Angiogenesis: a harmonized target for recovery after stroke. Stroke 43:2270–2274
Freedman SB, Vale P, Kalka C, Kearney M et al (2002) Plasma vascular endothelial growth factor (VEGF) levels after intramuscular and intramyocardial gene transfer of VEGF-1 plasmid DNA. Hum Gene Ther 13:1595–1603
Henry TD, Annex BH, McKendall GR et al (2003) The VIVA trial: vascular endothelial growth factor in ischemia for vascular angiogenesis. Circulation 107:1359–1365
Acknowledgments
The work of KG and BS is supported by grants from the German Research Foundation (DFG) KFO 136 and SFB 566/b9 and from the Federal Ministry of Education and Research (BMBF) 01GU0711.
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Grote, K., Schütt, H., Schieffer, B. (2013). Toll-Like Receptor-Linked Signal Transduction in Angiogenesis. In: Mehta, J., Dhalla, N. (eds) Biochemical Basis and Therapeutic Implications of Angiogenesis. Advances in Biochemistry in Health and Disease, vol 6. Springer, New York, NY. https://doi.org/10.1007/978-1-4614-5857-9_9
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DOI: https://doi.org/10.1007/978-1-4614-5857-9_9
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