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Inflammatory lymphangiogenesis: cellular mediators and functional implications

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Abstract

In adult mammals, lymphatic vessels have been shown to respond to their environment by undergoing lymphangiogenesis, the formation of new lymphatic vessels from preexisting ones. Accumulating experimental and preclinical studies demonstrate that lymphangiogenesis is associated with many inflammatory diseases and may represent an attractive therapeutic target for inflammatory diseases. Thus, a better understanding of how lymphangiogenesis is regulated and contribution to inflammation is critical and may benefit clinical research targeting chronic inflammatory diseases. This review discusses the biological functions of lymphangiogenesis during inflammation and our current understanding of the key cellular players that can either support or limit lymphangiogenesis. Current data suggest that the context and time frame in which lymphangiogenesis occurs will determine its impact on the course of inflammation.

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References

  1. Alitalo K (2011) The lymphatic vasculature in disease. Nat Med 17:1371–1380

    Article  PubMed  CAS  Google Scholar 

  2. Kim H, Kataru RP, Koh GY (2012) Regulation and implications of inflammatory lymphangiogenesis. Trends Immunol 33:350–356

    Article  PubMed  CAS  Google Scholar 

  3. Kerjaschki D, Regele HM, Moosberger I, Nagy-Bojarski K, Watschinger B, Soleiman A, Birner P, Krieger S, Hovorka A, Silberhumer G, Laakkonen P, Petrova T, Langer B, Raab I (2004) Lymphatic neoangiogenesis in human kidney transplants is associated with immunologically active lymphocytic infiltrates. J Am Soc Nephrol 15:603–612

    Article  PubMed  CAS  Google Scholar 

  4. Kerjaschki D, Huttary N, Raab I, Regele H, Bojarski-Nagy K, Bartel G, Krober SM, Greinix H, Rosenmaier A, Karlhofer F, Wick N, Mazal PR (2006) Lymphatic endothelial progenitor cells contribute to de novo lymphangiogenesis in human renal transplants. Nat Med 12:230–234

    Article  PubMed  CAS  Google Scholar 

  5. Cursiefen C, Cao J, Chen L, Liu Y, Maruyama K, Jackson D, Kruse FE, Wiegand SJ, Dana MR, Streilein JW (2004) Inhibition of hemangiogenesis and lymphangiogenesis after normal-risk corneal transplantation by neutralizing VEGF promotes graft survival. Invest Ophthalmol Vis Sci 45:2666–2673

    Article  PubMed  Google Scholar 

  6. Dietrich T, Onderka J, Bock F, Kruse FE, Vossmeyer D, Stragies R, Zahn G, Cursiefen C (2007) Inhibition of inflammatory lymphangiogenesis by integrin alpha5 blockade. Am J Pathol 171:361–372

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  7. Chen L, Hamrah P, Cursiefen C, Zhang Q, Pytowski B, Streilein JW, Dana MR (2004) Vascular endothelial growth factor receptor-3 mediates induction of corneal alloimmunity. Nat Med 10:813–815

    Article  PubMed  CAS  Google Scholar 

  8. Fogt F, Pascha TL, Zhang PJ, Gausas RE, Rahemtulla A, Zimmerman RL (2004) Proliferation of D2-40-expressing intestinal lymphatic vessels in the lamina propria in inflammatory bowel disease. Int J Mol Med 13:211–214

    PubMed  CAS  Google Scholar 

  9. Kaiserling E, Krober S, Geleff S (2003) Lymphatic vessels in the colonic mucosa in ulcerative colitis. Lymphology 36:52–61

    PubMed  CAS  Google Scholar 

  10. Pedica F, Ligorio C, Tonelli P, Bartolini S, Baccarini P (2008) Lymphangiogenesis in Crohn’s disease: an immunohistochemical study using monoclonal antibody D2-40. Virchows Arch 452:57–63

    Article  PubMed  CAS  Google Scholar 

  11. Geleff S, Schoppmann SF, Oberhuber G (2003) Increase in podoplanin-expressing intestinal lymphatic vessels in inflammatory bowel disease. Virchows Arch 442:231–237

    PubMed  Google Scholar 

  12. Zhang Q, Lu Y, Proulx ST, Guo R, Yao Z, Schwarz EM, Boyce BF, Xing L (2007) Increased lymphangiogenesis in joints of mice with inflammatory arthritis. Arthr Res Ther 9:R118

    Article  CAS  Google Scholar 

  13. Xu H, Edwards J, Banerji S, Prevo R, Jackson DG, Athanasou NA (2003) Distribution of lymphatic vessels in normal and arthritic human synovial tissues. Ann Rheum Dis 62:1227–1229

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  14. Wilkinson LS, Edwards JC (1991) Demonstration of lymphatics in human synovial tissue. Rheumatol Int 11:151–155

    Article  PubMed  CAS  Google Scholar 

  15. Yao LC, Baluk P, Feng J, McDonald DM (2010) Steroid-resistant lymphatic remodeling in chronically inflamed mouse airways. Am J Pathol 176:1525–1541

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  16. Baluk P, Tammela T, Ator E, Lyubynska N, Achen MG, Hicklin DJ, Jeltsch M, Petrova TV, Pytowski B, Stacker SA, Yla-Herttuala S, Jackson DG, Alitalo K, McDonald DM (2005) Pathogenesis of persistent lymphatic vessel hyperplasia in chronic airway inflammation. J Clin Invest 115:247–257

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  17. Kunstfeld R, Hirakawa S, Hong YK, Schacht V, Lange-Asschenfeldt B, Velasco P, Lin C, Fiebiger E, Wei X, Wu Y, Hicklin D, Bohlen P, Detmar M (2004) Induction of cutaneous delayed-type hypersensitivity reactions in VEGF-A transgenic mice results in chronic skin inflammation associated with persistent lymphatic hyperplasia. Blood 104:1048–1057

    Article  PubMed  CAS  Google Scholar 

  18. Kajiya K, Kunstfeld R, Detmar M, Chung JH (2007) Reduction of lymphatic vessels in photodamaged human skin. J Dermatol Sci 47:241–243

    Article  PubMed Central  PubMed  Google Scholar 

  19. Sugaya M, Kuwano Y, Suga H, Miyagaki T, Ohmatsu H, Kadono T, Okochi H, Blauvelt A, Tamaki K, Sato S (2012) Lymphatic dysfunction impairs antigen-specific immunization, but augments tissue swelling following contact with allergens. J Invest Dermatol 132:667–676

    Article  PubMed  CAS  Google Scholar 

  20. Tammela T, Alitalo K (2010) Lymphangiogenesis: molecular mechanisms and future promise. Cell 140:460–476

    Article  PubMed  CAS  Google Scholar 

  21. Cursiefen C, Maruyama K, Bock F, Saban D, Sadrai Z, Lawler J, Dana R, Masli S (2011) Thrombospondin 1 inhibits inflammatory lymphangiogenesis by CD36 ligation on monocytes. J Exp Med 208:1083–1092

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  22. Kataru RP, Jung K, Jang C, Yang H, Schwendener RA, Baik JE, Han SH, Alitalo K, Koh GY (2009) Critical role of CD11b + macrophages and VEGF in inflammatory lymphangiogenesis, antigen clearance, and inflammation resolution. Blood 113:5650–5659

    Article  PubMed  CAS  Google Scholar 

  23. Maruyama K, Ii M, Cursiefen C, Jackson DG, Keino H, Tomita M, Van Rooijen N, Takenaka H, D’Amore PA, Stein-Streilein J, Losordo DW, Streilein JW (2005) Inflammation-induced lymphangiogenesis in the cornea arises from CD11b-positive macrophages. J Clin Invest 115:2363–2372

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  24. Cursiefen C, Chen L, Borges LP, Jackson D, Cao J, Radziejewski C, D’Amore PA, Dana MR, Wiegand SJ, Streilein JW (2004) VEGF-A stimulates lymphangiogenesis and hemangiogenesis in inflammatory neovascularization via macrophage recruitment. J Clin Invest 113:1040–1050

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  25. Kang S, Lee SP, Kim KE, Kim HZ, Memet S, Koh GY (2009) Toll-like receptor 4 in lymphatic endothelial cells contributes to LPS-induced lymphangiogenesis by chemotactic recruitment of macrophages. Blood 113:2605–2613

    Article  PubMed  CAS  Google Scholar 

  26. Kim KE, Koh YJ, Jeon BH, Jang C, Han J, Kataru RP, Schwendener RA, Kim JM, Koh GY (2009) Role of CD11b+ macrophages in intraperitoneal lipopolysaccharide-induced aberrant lymphangiogenesis and lymphatic function in the diaphragm. Am J Pathol 175:1733–1745

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  27. Kubota Y, Takubo K, Shimizu T, Ohno H, Kishi K, Shibuya M, Saya H, Suda T (2009) M-CSF inhibition selectively targets pathological angiogenesis and lymphangiogenesis. J Exp Med 206:1089–1102

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  28. Muniz LR, Pacer ME, Lira SA, Furtado GC (2011) A critical role for dendritic cells in the formation of lymphatic vessels within tertiary lymphoid structures. J Immunol 187:828–834

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  29. Hamrah P, Chen L, Zhang Q, Dana MR (2003) Novel expression of vascular endothelial growth factor receptor (VEGFR)-3 and VEGF-C on corneal dendritic cells. Am J Pathol 163:57–68

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  30. Kanao T, Miyachi Y (2006) Lymphangiogenesis promotes lens destruction and subsequent lens regeneration in the newt eyeball, and both processes can be accelerated by transplantation of dendritic cells. Dev Biol 290:118–124

    Article  PubMed  CAS  Google Scholar 

  31. Angeli V, Ginhoux F, Llodra J, Quemeneur L, Frenette PS, Skobe M, Jessberger R, Merad M, Randolph GJ (2006) B cell-driven lymphangiogenesis in inflamed lymph nodes enhances dendritic cell mobilization. Immunity 24:203–215

    Article  PubMed  CAS  Google Scholar 

  32. Liao S, Ruddle NH (2006) Synchrony of high endothelial venules and lymphatic vessels revealed by immunization. J Immunol 177:3369–3379

    Article  PubMed  CAS  Google Scholar 

  33. Shrestha B, Hashiguchi T, Ito T, Miura N, Takenouchi K, Oyama Y, Kawahara K, Tancharoen S, Ki IY, Arimura N, Yoshinaga N, Noma S, Shrestha C, Nitanda T, Kitajima S, Arimura K, Sato M, Sakamoto T, Maruyama I (2010) B cell-derived vascular endothelial growth factor A promotes lymphangiogenesis and high endothelial venule expansion in lymph nodes. J Immunol 184:4819–4826

    Article  PubMed  CAS  Google Scholar 

  34. Tan KW, Chong SZ, Wong FH, Evrard M, Tan SM, Keeble J, Kemeny DM, Ng LG, Abastado JP, Angeli V (2013) Neutrophils contribute to inflammatory lymphangiogenesis by increasing VEGF-A bioavailability and secreting VEGF-D. Blood 122:3666–3677

    Article  PubMed  CAS  Google Scholar 

  35. Furtado GC, Marinkovic T, Martin AP, Garin A, Hoch B, Hubner W, Chen BK, Genden E, Skobe M, Lira SA (2007) Lymphotoxin beta receptor signaling is required for inflammatory lymphangiogenesis in the thyroid. Proc Natl Acad Sci USA 104:5026–5031

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  36. Kataru RP, Kim H, Jang C, Choi DK, Koh BI, Kim M, Gollamudi S, Kim YK, Lee SH, Koh GY (2011) T lymphocytes negatively regulate lymph node lymphatic vessel formation. Immunity 34:96–107

    Article  PubMed  CAS  Google Scholar 

  37. Halin C, Tobler NE, Vigl B, Brown LF, Detmar M (2007) VEGF-A produced by chronically inflamed tissue induces lymphangiogenesis in draining lymph nodes. Blood 110:3158–3167

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  38. Wuest TR, Carr DJ (2010) VEGF-A expression by HSV-1-infected cells drives corneal lymphangiogenesis. J Exp Med 207:101–115

    Article  PubMed Central  PubMed  Google Scholar 

  39. Chyou S, Ekland EH, Carpenter AC, Tzeng TC, Tian S, Michaud M, Madri JA, Lu TT (2008) Fibroblast-type reticular stromal cells regulate the lymph node vasculature. J Immunol 181:3887–3896

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  40. Tan KW, Yeo KP, Wong FH, Lim HY, Khoo KL, Abastado JP, Angeli V (2012) Expansion of cortical and medullary sinuses restrains lymph node hypertrophy during prolonged inflammation. J Immunol 188:4065–4080

    Article  PubMed  CAS  Google Scholar 

  41. Grigorova IL, Panteleev M, Cyster JG (2010) Lymph node cortical sinus organization and relationship to lymphocyte egress dynamics and antigen exposure. Proc Natl Acad Sci USA 107:20447–20452

    Article  PubMed Central  PubMed  Google Scholar 

  42. Weber M, Hauschild R, Schwarz J, Moussion C, de Vries I, Legler DF, Luther SA, Bollenbach T, Sixt M (2013) Interstitial dendritic cell guidance by haptotactic chemokine gradients. Science 339:328–332

    Article  PubMed  CAS  Google Scholar 

  43. Pflicke H, Sixt M (2009) Preformed portals facilitate dendritic cell entry into afferent lymphatic vessels. J Exp Med 206:2925–2935

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  44. Lammermann T, Bader BL, Monkley SJ, Worbs T, Wedlich-Soldner R, Hirsch K, Keller M, Forster R, Critchley DR, Fassler R, Sixt M (2008) Rapid leukocyte migration by integrin-independent flowing and squeezing. Nature 453:51–55

    Article  PubMed  CAS  Google Scholar 

  45. Acton SE, Astarita JL, Malhotra D, Lukacs-Kornek V, Franz B, Hess PR, Jakus Z, Kuligowski M, Fletcher AL, Elpek KG, Bellemare-Pelletier A, Sceats L, Reynoso ED, Gonzalez SF, Graham DB, Chang J, Peters A, Woodruff M, Kim YA, Swat W, Morita T, Kuchroo V, Carroll MC, Kahn ML, Wucherpfennig KW, Turley SJ (2012) Podoplanin-rich stromal networks induce dendritic cell motility via activation of the C-type lectin receptor CLEC-2. Immunity 37:276–289

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  46. Salmi M, Koskinen K, Henttinen T, Elima K, Jalkanen S (2004) CLEVER-1 mediates lymphocyte transmigration through vascular and lymphatic endothelium. Blood 104:3849–3857

    Article  PubMed  CAS  Google Scholar 

  47. Braun A, Worbs T, Moschovakis GL, Halle S, Hoffmann K, Bolter J, Munk A, Forster R (2011) Afferent lymph-derived T cells and DCs use different chemokine receptor CCR7-dependent routes for entry into the lymph node and intranodal migration. Nat Immunol 12:879–887

    Article  PubMed  CAS  Google Scholar 

  48. Debes GF, Arnold CN, Young AJ, Krautwald S, Lipp M, Hay JB, Butcher EC (2005) Chemokine receptor CCR7 required for T lymphocyte exit from peripheral tissues. Nat Immunol 6:889–894

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  49. Bromley SK, Yan S, Tomura M, Kanagawa O, Luster AD (2013) Recirculating memory T cells are a unique subset of CD4 + T cells with a distinct phenotype and migratory pattern. J Immunol 190:970–976

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  50. Bromley SK, Thomas SY, Luster AD (2005) Chemokine receptor CCR7 guides T cell exit from peripheral tissues and entry into afferent lymphatics. Nat Immunol 6:895–901

    Article  PubMed  CAS  Google Scholar 

  51. Tomura M, Honda T, Tanizaki H, Otsuka A, Egawa G, Tokura Y, Waldmann H, Hori S, Cyster JG, Watanabe T, Miyachi Y, Kanagawa O, Kabashima K (2010) Activated regulatory T cells are the major T cell type emigrating from the skin during a cutaneous immune response in mice. J Clin Invest 120:883–893

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  52. Johnson LA, Jackson DG (2010) Inflammation-induced secretion of CCL21 in lymphatic endothelium is a key regulator of integrin-mediated dendritic cell transmigration. Int Immunol 22:839

    Article  PubMed  CAS  Google Scholar 

  53. Tal O, Lim HY, Gurevich I, Milo I, Shipony Z, Ng LG, Angeli V, Shakhar G (2011) DC mobilization from the skin requires docking to immobilized CCL21 on lymphatic endothelium and intralymphatic crawling. J Exp Med 208:2141–2153

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  54. Johnson LA, Clasper S, Holt AP, Lalor PF, Baban D, Jackson DG (2006) An inflammation-induced mechanism for leukocyte transmigration across lymphatic vessel endothelium. J Exp Med 203:2763–2777

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  55. Vigl B, Aebischer D, Nitschke M, Iolyeva M, Rothlin T, Antsiferova O, Halin C (2011) Tissue inflammation modulates gene expression of lymphatic endothelial cells and dendritic cell migration in a stimulus-dependent manner. Blood 118:205–215

    Article  PubMed  CAS  Google Scholar 

  56. Lee KM, McKimmie CS, Gilchrist DS, Pallas KJ, Nibbs RJ, Garside P, McDonald V, Jenkins C, Ransohoff R, Liu L, Milling S, Cerovic V, Graham GJ (2011) D6 facilitates cellular migration and fluid flow to lymph nodes by suppressing lymphatic congestion. Blood 118:6220–6229

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  57. McKimmie CS, Singh MD, Hewit K, Lopez-Franco O, Le Brocq M, Rose-John S, Lee KM, Baker AH, Wheat R, Blackbourn DJ, Nibbs RJ, Graham GJ (2013) An analysis of the function and expression of D6 on lymphatic endothelial cells. Blood 121:3768–3777

    Article  PubMed  CAS  Google Scholar 

  58. Grigorova IL, Schwab SR, Phan TG, Pham TH, Okada T, Cyster JG (2009) Cortical sinus probing, S1P1-dependent entry and flow-based capture of egressing T cells. Nat Immunol 10:58–65

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  59. Pham TH, Okada T, Matloubian M, Lo CG, Cyster JG (2008) S1P1 receptor signaling overrides retention mediated by G alpha i-coupled receptors to promote T cell egress. Immunity 28:122–133

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  60. Schwab SR, Cyster JG (2007) Finding a way out: lymphocyte egress from lymphoid organs. Nat Immunol 8:1295–1301

    Article  PubMed  CAS  Google Scholar 

  61. Pham TH, Baluk P, Xu Y, Grigorova I, Bankovich AJ, Pappu R, Coughlin SR, McDonald DM, Schwab SR, Cyster JG (2010) Lymphatic endothelial cell sphingosine kinase activity is required for lymphocyte egress and lymphatic patterning. J Exp Med 207:17–27

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  62. Lee JW, Epardaud M, Sun J, Becker JE, Cheng AC, Yonekura AR, Heath JK, Turley SJ (2007) Peripheral antigen display by lymph node stroma promotes T cell tolerance to intestinal self. Nat Immunol 8:181–190

    Article  PubMed  CAS  Google Scholar 

  63. Gardner JM, Devoss JJ, Friedman RS, Wong DJ, Tan YX, Zhou X, Johannes KP, Su MA, Chang HY, Krummel MF, Anderson MS (2008) Deletional tolerance mediated by extrathymic Aire-expressing cells. Science 321:843–847

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  64. Nichols LA, Chen Y, Colella TA, Bennett CL, Clausen BE, Engelhard VH (2007) Deletional self-tolerance to a melanocyte/melanoma antigen derived from tyrosinase is mediated by a radio-resistant cell in peripheral and mesenteric lymph nodes. J Immunol 179:993–1003

    Article  PubMed  CAS  Google Scholar 

  65. Cohen JN, Guidi CJ, Tewalt EF, Qiao H, Rouhani SJ, Ruddell A, Farr AG, Tung KS, Engelhard VH (2010) Lymph node-resident lymphatic endothelial cells mediate peripheral tolerance via Aire-independent direct antigen presentation. J Exp Med 207:681–688

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  66. Tewalt EF, Cohen JN, Rouhani SJ, Guidi CJ, Qiao H, Fahl SP, Conaway MR, Bender TP, Tung KS, Vella AT, Adler AJ, Chen L, Engelhard VH (2012) Lymphatic endothelial cells induce tolerance via PD-L1 and lack of costimulation leading to high-level PD-1 expression on CD8 T cells. Blood 120:4772–4782

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  67. Fletcher AL, Lukacs-Kornek V, Reynoso ED, Pinner SE, Bellemare-Pelletier A, Curry MS, Collier AR, Boyd RL, Turley SJ (2010) Lymph node fibroblastic reticular cells directly present peripheral tissue antigen under steady-state and inflammatory conditions. J Exp Med 207:689–697

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  68. Lukacs-Kornek V, Malhotra D, Fletcher AL, Acton SE, Elpek KG, Tayalia P, Collier AR, Turley SJ (2011) Regulated release of nitric oxide by nonhematopoietic stroma controls expansion of the activated T cell pool in lymph nodes. Nat Immunol 12:1096–1104

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  69. Siegert S, Huang HY, Yang CY, Scarpellino L, Carrie L, Essex S, Nelson PJ, Heikenwalder M, Acha-Orbea H, Buckley CD, Marsland BJ, Zehn D, Luther SA (2011) Fibroblastic reticular cells from lymph nodes attenuate T cell expansion by producing nitric oxide. PLoS ONE 6:e27618

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  70. Khan O, Headley M, Gerard A, Wei W, Liu L, Krummel MF (2011) Regulation of T cell priming by lymphoid stroma. PLoS ONE 6:e26138

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  71. Podgrabinska S, Kamalu O, Mayer L, Shimaoka M, Snoeck H, Randolph GJ, Skobe M (2009) Inflamed lymphatic endothelium suppresses dendritic cell maturation and function via Mac-1/ICAM-1-dependent mechanism. J Immunol 183:1767–1779

    Article  PubMed  CAS  Google Scholar 

  72. Kajiya K, Hirakawa S, Detmar M (2006) Vascular endothelial growth factor-A mediates ultraviolet B-induced impairment of lymphatic vessel function. Am J Pathol 169:1496–1503

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  73. Shi VY, Bao L, Chan LS (2012) Inflammation-driven dermal lymphangiogenesis in atopic dermatitis is associated with CD11b + macrophage recruitment and VEGF-C up-regulation in the IL-4-transgenic mouse model. Microcirculation 19:567–579

    Article  PubMed  CAS  Google Scholar 

  74. Bachmann BO, Luetjen-Drecoll E, Bock F, Wiegand SJ, Hos D, Dana R, Kruse FE, Cursiefen C (2009) Transient postoperative vascular endothelial growth factor (VEGF)-neutralisation improves graft survival in corneas with partly regressed inflammatory neovascularisation. Br J Ophthalmol 93:1075–1080

    Article  PubMed  CAS  Google Scholar 

  75. Bachmann BO, Bock F, Wiegand SJ, Maruyama K, Dana MR, Kruse FE, Luetjen-Drecoll E, Cursiefen C (2008) Promotion of graft survival by vascular endothelial growth factor a neutralization after high-risk corneal transplantation. Arch Ophthalmol 126:71–77

    Article  PubMed  Google Scholar 

  76. Dietrich T, Bock F, Yuen D, Hos D, Bachmann BO, Zahn G, Wiegand S, Chen L, Cursiefen C (2010) Cutting edge: lymphatic vessels, not blood vessels, primarily mediate immune rejections after transplantation. J Immunol 184:535–539

    Article  PubMed  CAS  Google Scholar 

  77. Kajiya K, Sawane M, Huggenberger R, Detmar M (2009) Activation of the VEGFR-3 pathway by VEGF-C attenuates UVB-induced edema formation and skin inflammation by promoting lymphangiogenesis. J Invest Dermatol 129:1292–1298

    Article  PubMed  CAS  Google Scholar 

  78. Huggenberger R, Ullmann S, Proulx ST, Pytowski B, Alitalo K, Detmar M (2010) Stimulation of lymphangiogenesis via VEGFR-3 inhibits chronic skin inflammation. J Exp Med 207:2255

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  79. Huggenberger R, Siddiqui SS, Brander D, Ullmann S, Zimmermann K, Antsiferova M, Werner S, Alitalo K, Detmar M (2011) An important role of lymphatic vessel activation in limiting acute inflammation. Blood 117:4667–4678

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  80. Guo R, Zhou Q, Proulx ST, Wood R, Ji RC, Ritchlin CT, Pytowski B, Zhu Z, Wang YJ, Schwarz EM, Xing L (2009) Inhibition of lymphangiogenesis and lymphatic drainage via vascular endothelial growth factor receptor 3 blockade increases the severity of inflammation in a mouse model of chronic inflammatory arthritis. Arthr Rheum 60:2666–2676

    Article  CAS  Google Scholar 

  81. Polzer K, Baeten D, Soleiman A, Distler J, Gerlag DM, Tak PP, Schett G, Zwerina J (2008) Tumour necrosis factor blockade increases lymphangiogenesis in murine and human arthritic joints. Ann Rheum Dis 67:1610–1616

    Article  PubMed  CAS  Google Scholar 

  82. Proulx ST, Kwok E, You Z, Beck CA, Shealy DJ, Ritchlin CT, Boyce BF, Xing L, Schwarz EM (2007) MRI and quantification of draining lymph node function in inflammatory arthritis. Ann N Y Acad Sci 1117:106–123

    Article  PubMed  Google Scholar 

  83. Drayton DL, Liao S, Mounzer RH, Ruddle NH (2006) Lymphoid organ development: from ontogeny to neogenesis. Nat Immunol 7:344–353

    Article  PubMed  CAS  Google Scholar 

  84. Aloisi F, Pujol-Borrell R (2006) Lymphoid neogenesis in chronic inflammatory diseases. Nat Rev Immunol 6:205–217

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

This work was supported by Biomedical Research Council, National Medical Research Council and National Research Foundation.

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  1. Singapore Immunology Network, BMSI, A-STAR, Singapore, Singapore

    Kar Wai Tan & Shu Zhen Chong

  2. Immunology Programme, Department of Microbiology, Centre for Life Sciences, Yong Loo Lin School of Medicine, National University of Singapore, #03-05, 28 Medical Drive, Singapore, 117456, Singapore

    Véronique Angeli

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Tan, K.W., Chong, S.Z. & Angeli, V. Inflammatory lymphangiogenesis: cellular mediators and functional implications. Angiogenesis 17, 373–381 (2014). https://doi.org/10.1007/s10456-014-9419-4

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