Stimulation of lymphangiogenesis via VEGFR-3 inhibits chronic skin inflammation

Journal of Experimental Medicine

Volumn 207, Issue 10, 2010, Pages 2255-2269

  Huggenberger, Reto ^a   Ullmann, Stefan ^a   Proulx, Steven T ^a   Pytowski, Bronislaw ^b   Alitalo, Kari ^c   Detmar, Michael ^a  

^a ETH ZURICH   (Switzerland)

^b ELI LILLY AND COMPANY   (United States)

^c UNIVERSITY OF HELSINKI   (Finland)

Author keywords

[No Author keywords available]

Indexed keywords

CYTOKERATIN 14; VASCULOTROPIN A; VASCULOTROPIN D; VASCULOTROPIN RECEPTOR 2; VASCULOTROPIN RECEPTOR 3;

ANGIOGENESIS; ANIMAL EXPERIMENT; ANIMAL MODEL; ANIMAL TISSUE; ARTICLE; CD8+ T LYMPHOCYTE; CELL DIFFERENTIATION; CHRONIC INFLAMMATION; EDEMA; ENZYME LINKED IMMUNOSORBENT ASSAY; EPIDERMIS HYPERPLASIA; EXPERIMENTAL MODEL; EXPERIMENTAL MOUSE; INFLAMMATORY CELL; LYMPH VESSEL; LYMPHANGIOGENESIS; LYMPHATIC DRAINAGE; MOUSE; NONHUMAN; NUCLEOTIDE SEQUENCE; PRIORITY JOURNAL; REVERSE TRANSCRIPTION POLYMERASE CHAIN REACTION; SKIN INFLAMMATION; TRANSGENIC MOUSE;

ANIMALS; ANTIBODIES, BLOCKING; CD8-POSITIVE T-LYMPHOCYTES; CHRONIC DISEASE; DERMATITIS; KERATIN-14; LYMPHANGIOGENESIS; MICE; MICE, TRANSGENIC; SKIN; VASCULAR ENDOTHELIAL GROWTH FACTOR A; VASCULAR ENDOTHELIAL GROWTH FACTOR D; VASCULAR ENDOTHELIAL GROWTH FACTOR RECEPTOR-2; VASCULAR ENDOTHELIAL GROWTH FACTOR RECEPTOR-3;

EID: 77957742772     PISSN: 00221007     EISSN: 15409538     Source Type: Journal    
DOI: 10.1084/jem.20100559     Document Type: Article

References (60)

1. Adams, R.H., and K. Alitalo. 2007. Molecular regulation of angiogenesis and lymphangiogenesis. Nat. Rev. Mol. Cell Biol. 8:464-478. doi:10.1038/nrm2183
2. Angeli, V., F. Ginhoux, J. Llodrà, L. Quemeneur, P.S. Frenette, M. Skobe, R. Jessberger, M. Merad, and G.J. Randolph. 2006. B cell-driven lymphangiogenesis in inflamed lymph nodes enhances dendritic cell mobilization. Immunity. 24:203-215. doi:10.1016/j.immuni.2006.01.003 (Pubitemid 43214589)
3. Bainbridge, J., B. Sivakumar, and E. Paleolog. 2006. Angiogenesis as a therapeutic target in arthritis: lessons from oncology. Curr. Pharm. Des. 12:2631-2644. doi:10.2174/138161206777698747
4. Baldwin, M.E., B. Catimel, E.C. Nice, S. Roufail, N.E. Hall, K.L. Stenvers, M.J. Karkkainen, K. Alitalo, S.A. Stacker, and M.G. Achen. 2001. The specificity of receptor binding by vascular endothelial growth factor-d is different in mouse and man. J. Biol. Chem. 276:19166-19171. doi:10.1074/jbc. M100097200
5. Baluk, P., T. Tammela, E. Ator, N. Lyubynska, M.G. Achen, D.J. Hicklin, M. Jeltsch, T.V. Petrova, B. Pytowski, S.A. Stacker, et al. 2005. Pathogenesis of persistent lymphatic vessel hyperplasia in chronic airway inflammation. J. Clin. Invest. 115:247-257.
6. Bhushan, M., B. McLaughlin, J.B. Weiss, and C.E. Griffiths. 1999. Levels of endothelial cell stimulating angiogenesis factor and vascular endothelial growth factor are elevated in psoriasis. Br. J. Dermatol. 141:1054-1060. doi:10.1046/j.1365-2133.1999.03205.x (Pubitemid 30046195)
7. Carmeliet, P. 2003. Angiogenesis in health and disease. Nat. Med. 9:653-660. doi:10.1038/nm0603-653
8. Cursiefen, C., J. Cao, L. Chen, Y. Liu, K. Maruyama, D. Jackson, F.E. Kruse, S.J. Wiegand, M.R. Dana, and J.W. Streilein. 2004. Inhibition of hemangiogenesis and lymphangiogenesis after normal-risk corneal transplantation by neutralizing VEGF promotes graft survival. Invest. Ophthalmol. Vis. Sci. 45:2666-2673. doi:10.1167/iovs.03-1380
9. Danese, S., M. Sans, C. de la Motte, C. Graziani, G. West, M.H. Phillips, R. Pola, S. Rutella, J. Willis, A. Gasbarrini, and C. Fiocchi. 2006. Angiogenesis as a novel component of inflammatory bowel disease pathogenesis. Gastroenterology. 130:2060-2073. doi:10.1053/j.gastro.2006.03.054 (Pubitemid 43816964)
10. Detmar, M., L.F. Brown, K.P. Claffey, K.T. Yeo, O. Kocher, R.W. Jackman, B. Berse, and H.F. Dvorak. 1994. Overexpression of vascular permeability factor/vascular endothelial growth factor and its receptors in psoriasis. J. Exp. Med. 180:1141-1146. doi:10.1084/jem.180.3.1141
11. Detmar, M., L.F. Brown, M.P. Schön, B.M. Elicker, P. Velasco, L. Richard, D. Fukumura, W. Monsky, K.P. Claffey, and R.K. Jain. 1998. Increased microvascular density and enhanced leukocyte rolling and adhesion in the skin of VEGF transgenic mice. J. Invest. Dermatol. 111:1-6. doi:10.1046/j.1523-1747. 1998.00262.x
12. Dixelius, J., T. Makinen, M. Wirzenius, M.J. Karkkainen, C. Wernstedt, K. Alitalo, and L. Claesson-Welsh. 2003. Ligand-induced vascular endothelial growth factor receptor-3 (VEGFR-3) heterodimerization with VEGFR-2 in primary lymphatic endothelial cells regulates tyrosine phosphorylation sites. J. Biol. Chem. 278:40973-40979. doi:10.1074/jbc.M304499200 (Pubitemid 37280919)
13. Guo, R., Q. Zhou, S.T. Proulx, R. Wood, R.C. Ji, C.T. Ritchlin, B. Pytowski, Z. Zhu, Y.J. Wang, E.M. Schwarz, and L. Xing. 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. Arthritis Rheum. 60:2666-2676. doi:10.1002/art.24764
14. Haiko, P., T. Makinen, S. Keskitalo, J. Taipale, M.J. Karkkainen, M.E. Baldwin, S.A. Stacker, M.G. Achen, and K. Alitalo. 2008. Deletion of vascular endothelial growth factor C (VEGF-C) and VEGF-D is not equivalent to VEGF receptor 3 deletion in mouse embryos. Mol. Cell. Biol. 28:4843-4850. doi:10.1128/MCB.02214-07
15. Halin, C., N.E. Tobler, B. Vigl, L.F. Brown, and M. Detmar. 2007. VEGF-A produced by chronically inflamed tissue induces lymphangiogenesis in draining lymph nodes. Blood. 110:3158-3167. doi:10.1182/blood-2007-01-066811
16. Halin, C., H. Fahrngruber, J.G. Meingassner, G. Bold, A. Littlewood-Evans, A. Stuetz, and M. Detmar. 2008. Inhibition of chronic and acute skin inflammation by treatment with a vascular endothelial growth factor receptor tyrosine kinase inhibitor. Am. J. Pathol. 173:265-277. doi:10.2353/ajpath.2008.071074
17. Hamrah, P., L. Chen, Q. Zhang, and M.R. Dana. 2003. Novel expression of vascular endothelial growth factor receptor (VEGFR)-3 and VEGF-C on corneal dendritic cells. Am. J. Pathol. 163:57-68.
18. Hamrah, P., L. Chen, C. Cursiefen, Q. Zhang, N.C. Joyce, and M.R. Dana. 2004. Expression of vascular endothelial growth factor receptor-3 (VEGFR-3) on monocytic bone marrow-derived cells in the conjunctiva. Exp. Eye Res. 79:553-561. doi:10.1016/j.exer.2004.06.028
19. Hirakawa, S., S. Kodama, R. Kunstfeld, K. Kajiya, L.F. Brown, and M. Detmar. 2005. VEGF-A induces tumor and sentinel lymph node lymphangiogenesis and promotes lymphatic metastasis. J. Exp. Med. 201:1089-1099. doi:10.1084/jem. 20041896
20. Hoshida, T., N. Isaka, J. Hagendoorn, E. di Tomaso, Y.L. Chen, B. Pytowski, D. Fukumura, T.P. Padera, and R.K. Jain. 2006. Imaging steps of lymphatic metastasis reveals that vascular endothelial growth factor-C increases metastasis by increasing delivery of cancer cells to lymph nodes: therapeutic implications. Cancer Res. 66:8065-8075. doi:10.1158/0008-5472.CAN-06-1392
21. Hvid, H., I. Teige, P.H. Kvist, L. Svensson, and K. Kemp. 2008. TPA induction leads to a Th17-like response in transgenic K14/VEGF mice: a novel in vivo screening model of psoriasis. Int. Immunol. 20:1097-1106. doi:10.1093/intimm/dxn068
22. Jamieson, T., D.N. Cook, R.J. Nibbs, A. Rot, C. Nixon, P. McLean, A. Alcami, S.A. Lira, M. Wiekowski, and G.J. Graham. 2005. The chemokine receptor D6 limits the inflammatory response in vivo. Nat. Immunol. 6:403-411. doi:10.1038/ni1182
23. Jeltsch, M., A. Kaipainen, V. Joukov, X. Meng, M. Lakso, H. Rauvala, M. Swartz, D. Fukumura, R.K. Jain, and K. Alitalo. 1997. Hyperplasia of lymphatic vessels in VEGF-C transgenic mice. Science. 276:1423-1425. doi:10.1126/science. 276.5317.1423
24. Joukov, V., T. Sorsa, V. Kumar, M. Jeltsch, L. Claesson-Welsh, Y. Cao, O. Saksela, N. Kalkkinen, and K. Alitalo. 1997. Proteolytic processing regulates receptor specificity and activity of VEGF-C. EMBO J. 16:3898-3911. doi:10.1093/emboj/16.13.3898 (Pubitemid 27281006)
25. Joukov, V., V. Kumar, T. Sorsa, E. Arighi, H. Weich, O. Saksela, and K. Alitalo. 1998. A recombinant mutant vascular endothelial growth factor-C that has lost vascular endothelial growth factor receptor-2 binding, activation, and vascular permeability activities. J. Biol. Chem. 273:6599-6602. doi:10.1074/jbc.273.12.6599 (Pubitemid 28160314)
26. Kaipainen, A., J. Korhonen, T. Mustonen, V.W. van Hinsbergh, G.H. Fang, D. Dumont, M. Breitman, and K. Alitalo. 1995. Expression of the fms-like tyrosine kinase 4 gene becomes restricted to lymphatic endothelium during development. Proc. Natl. Acad. Sci. USA. 92:3566-3570. doi:10.1073/pnas.92.8. 3566
27. Kajiya, K., S. Hirakawa, and M. Detmar. 2006. Vascular endothelial growth factor-A mediates ultraviolet B-induced impairment of lymphatic vessel function. Am. J. Pathol. 169:1496-1503. doi:10.2353/ajpath.2006.060197 (Pubitemid 351194380)
28. Kanazawa, S., T. Tsunoda, E. Onuma, T. Majima, M. Kagiyama, and K. Kikuchi. 2001. VEGF, basic-FGF, and TGF-beta in Crohn's disease and ulcerative colitis: a novel mechanism of chronic intestinal inflammation. Am. J. Gastroenterol. 96:822-828. (Pubitemid 32240738)
29. Karkkainen, M.J., A. Saaristo, L. Jussila, K.A. Karila, E.C. Lawrence, K. Pajusola, H. Bueler, A. Eichmann, R. Kauppinen, M.I. Kettunen, et al. 2001. A model for gene therapy of human hereditary lymphedema. Proc. Natl. Acad. Sci. USA. 98:12677-12682. doi:10.1073/pnas.221449198
30. Karpanen, T., and K. Alitalo. 2008. Molecular biology and pathology of lymphangiogenesis. Annu. Rev. Pathol. 3:367-397. doi:10.1146/annurev. pathmechdis.3.121806.151515
31. Kataru, R.P., K. Jung, C. Jang, H. Yang, R.A. Schwendener, J.E. Baik, S.H. Han, K. Alitalo, and G.Y. Koh. 2009. Critical role of CD11b+ macrophages and VEGF in inflammatory lymphangiogenesis, antigen clearance, and inflammation resolution. Blood. 113:5650-5659. doi:10.1182/blood-2008-09-176776
32. Kerjaschki, D., H.M. Regele, I. Moosberger, K. Nagy-Bojarski, B. Watschinger, A. Soleiman, P. Birner, S. Krieger, A. Hovorka, G. Silberhumer, et al. 2004. Lymphatic neoangiogenesis in human kidney transplants is associated with immunologically active lymphocytic infiltrates. J. Am. Soc. Nephrol. 15:603-612. doi:10.1097/01.ASN.0000113316.52371.2E
33. Kiba, A., H. Sagara, T. Hara, and M. Shibuya. 2003. VEGFR-2-specific ligand VEGF-E induces non-edematous hyper-vascularization in mice. Biochem. Biophys. Res. Commun. 301:371-377. doi:10.1016/S0006-291X(02)03033-4 (Pubitemid 36279248)
34. Koch, A.E., L.A. Harlow, G.K. Haines, E.P. Amento, E.N. Unemori, W.L. Wong, R.M. Pope, and N. Ferrara. 1994. Vascular endothelial growth factor. A cytokine modulating endothelial function in rheumatoid arthritis. J. Immunol. 152:4149-4156.
35. Kriehuber, E., S. Breiteneder-Geleff, M. Groeger, A. Soleiman, S.F. Schoppmann, G. Stingl, D. Kerjaschki, and D. Maurer. 2001. Isolation and characterization of dermal lymphatic and blood endothelial cells reveal stable and functionally specialized cell lineages. J. Exp. Med. 194:797-808. doi:10.1084/jem.194.6.797
36. Krueger, G.G., R.G. Langley, C. Leonardi, N. Yeilding, C. Guzzo, Y. Wang, L.T. Dooley, and M. Lebwohl; CNTO 1275 Psoriasis Study Group. 2007. A human interleukin-12/23 monoclonal antibody for the treatment of psoriasis. N. Engl. J. Med. 356:580-592. doi:10.1056/NEJMoa062382
37. Kunstfeld, R., S. Hirakawa, Y.K. Hong, V. Schacht, B. Lange-Asschenfeldt, P. Velasco, C. Lin, E. Fiebiger, X. Wei, Y. Wu, et al. 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. doi:10.1182/blood-2003-08-2964
38. Louten, J., K. Boniface, and R. de Waal Malefyt. 2009. Development and function of TH17 cells in health and disease. J. Allergy Clin. Immunol. 123:1004-1011. doi:10.1016/j.jaci.2009.04.003
39. Mäkinen, T., L. Jussila, T. Veikkola, T. Karpanen, M.I. Kettunen, K.J. Pulkkanen, R. Kauppinen, D.G. Jackson, H. Kubo, S. Nishikawa, et al. 2001a. Inhibition of lymphangiogenesis with resulting lymphedema in transgenic mice expressing soluble VEGF receptor-3. Nat. Med. 7:199-205. doi:10.1038/84651
40. Mäkinen, T., T. Veikkola, S. Mustjoki, T. Karpanen, B. Catimel, E.C. Nice, L. Wise, A. Mercer, H. Kowalski, D. Kerjaschki, et al. 2001b. Isolated lymphatic endothelial cells transduce growth, survival and migratory signals via the VEGF-C/D receptor VEGFR-3. EMBO J. 20:4762-4773. doi:10.1093/emboj/20.17. 4762
41. Mumprecht, V., and M. Detmar. 2009. Lymphangiogenesis and cancer metastasis. J. Cell. Mol. Med. 13:1405-1416. doi:10.1111/j.1582-4934.2009.00834. x
42. Nagy, J.A., E. Vasile, D. Feng, C. Sundberg, L.F. Brown, M.J. Detmar, J.A. Lawitts, L. Benjamin, X. Tan, E.J. Manseau, et al. 2002. Vascular permeability factor/vascular endothelial growth factor induces lymphangiogenesis as well as angiogenesis. J. Exp. Med. 196:1497-1506. doi:10.1084/jem.20021244 (Pubitemid 35424943)
43. Nair, R.P., K.C. Duffin, C. Helms, J. Ding, P.E. Stuart, D. Goldgar, J.E. Gudjonsson, Y. Li, T. Tejasvi, B.J. Feng, et al; Collaborative Association Study of Psoriasis. 2009. Genome-wide scan reveals association of psoriasis with IL-23 and NF-kappaB pathways. Nat. Genet. 41:199-204. doi:10.1038/ng.311
44. Paavonen, K., P. Puolakkainen, L. Jussila, T. Jahkola, and K. Alitalo. 2000. Vascular endothelial growth factor receptor-3 in lymphangiogenesis in wound healing. Am. J. Pathol. 156:1499-1504. (Pubitemid 30646689)
45. Partanen, T.A., J. Arola, A. Saaristo, L. Jussila, A. Ora, M. Miettinen, S.A. Stacker, M.G. Achen, and K. Alitalo. 2000. VEGF-C and VEGF-D expression in neuroendocrine cells and their receptor, VEGFR-3, in fenestrated blood vessels in human tissues. FASEB J. 14:2087-2096. doi:10.1096/fj.99-1049com
46. Polzer, K., D. Baeten, A. Soleiman, J. Distler, D.M. Gerlag, P.P. Tak, G. Schett, and J. Zwerina. 2008. Tumour necrosis factor blockade increases lymphangiogenesis in murine and human arthritic joints. Ann. Rheum. Dis. 67:1610-1616. doi:10.1136/ard.2007.083394
47. Pytowski, B., J. Goldman, K. Persaud, Y. Wu, L. Witte, D.J. Hicklin, M. Skobe, K.C. Boardman, and M.A. Swartz. 2005. Complete and specific inhibition of adult lymphatic regeneration by a novel VEGFR-3 neutralizing antibody. J. Natl. Cancer Inst. 97:14-21. doi:10.1093/jnci/dji003
48. Schmittgen, T.D., and K.J. Livak. 2008. Analyzing real-time PCR data by the comparative C(T) method. Nat. Protoc. 3:1101-1108. doi:10.1038/nprot.2008.73
49. Schonthaler, H.B., R. Huggenberger, S.K. Wculek, M. Detmar, and E.F. Wagner. 2009. Systemic anti-VEGF treatment strongly reduces skin inflammation in a mouse model of psoriasis. Proc. Natl. Acad. Sci. USA. 106:21264-21269. doi:10.1073/pnas.0907550106
50. Stark, H.J., D. Breitkreutz, A. Limat, P. Bowden, and N.E. Fusenig. 1987. Keratins of the human hair follicle: "hyperproliferative" keratins consistently expressed in outer root sheath cells in vivo and in vitro. Differentiation. 35:236-248.
51. Szuba, A., M. Skobe, M.J. Karkkainen, W.S. Shin, D.P. Beynet, N.B. Rockson, N. Dakhil, S. Spilman, M.L. Goris, H.W. Strauss, et al. 2002. Therapeutic lymphangiogenesis with human recombinant VEGF-C. FASEB J. 16:1985-1987.
52. Tammela, T., A. Saaristo, T. Holopainen, J. Lyytikkä, A. Kotronen, M. Pitkonen, U. Abo-Ramadan, S. Ylä-Herttuala, T.V. Petrova, and K. Alitalo. 2007. Therapeutic differentiation and maturation of lymphatic vessels after lymph node dissection and transplantation. Nat. Med. 13:1458-1466. doi:10.1038/nm1689
53. Tammela, T., G. Zarkada, E. Wallgard, A. Murtomäki, S. Suchting, M. Wirzenius, M. Waltari, M. Hellström, T. Schomber, R. Peltonen, et al. 2008. Blocking VEGFR-3 suppresses angiogenic sprouting and vascular network formation. Nature. 454:656-660. doi:10.1038/nature07083
54. Valtola, R., P. Salven, P. Heikkilä, J. Taipale, H. Joensuu, M. Rehn, T. Pihlajaniemi, H. Weich, R. deWaal, and K. Alitalo. 1999. VEGFR-3 and its ligand VEGF-C are associated with angiogenesis in breast cancer. Am. J. Pathol. 154:1381-1390.
55. Van den Broeck, W., A. Derore, and P. Simoens. 2006. Anatomy and nomenclature of murine lymph nodes: Descriptive study and nomenclatory standardization in BALB/cAnNCrl mice. J. Immunol. Methods. 312:12-19. doi:10.1016/j.jim.2006.01.022 (Pubitemid 43795993)
56. Wirzenius, M., T. Tammela, M. Uutela, Y. He, T. Odorisio, G. Zambruno, J.A. Nagy, H.F. Dvorak, S. Ylä-Herttuala, M. Shibuya, and K. Alitalo. 2007. Distinct vascular endothelial growth factor signals for lymphatic vessel enlargement and sprouting. J. Exp. Med. 204:1431-1440. doi:10.1084/jem.20062642
57. Wuest, T.R., and D.J. Carr. 2010. VEGF-A expression by HSV-1-infected cells drives corneal lymphangiogenesis. J. Exp. Med. 207:101-115. doi:10.1084/jem.20091385
58. Xia, Y.P., B. Li, D. Hylton, M. Detmar, G.D. Yancopoulos, and J.S. Rudge. 2003. Transgenic delivery of VEGF to mouse skin leads to an inflammatory condition resembling human psoriasis. Blood. 102:161-168. doi:10.1182/blood- 2002-12-3793
59. Yoon, Y.S., T. Murayama, E. Gravereaux, T. Tkebuchava, M. Silver, C. Curry, A. Wecker, R. Kirchmair, C.S. Hu, M. Kearney, et al. 2003. VEGF-C gene therapy augments postnatal lymphangiogenesis and ameliorates secondary lymphedema. J. Clin. Invest. 111:717-725.
60. Zhang, Q., Y. Lu, S.T. Proulx, R. Guo, Z. Yao, E.M. Schwarz, B.F. Boyce, and L. Xing. 2007. Increased lymphangiogenesis in joints of mice with inflammatory arthritis. Arthritis Res. Ther. 9:R118. doi:10.1186/ar2326