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Published in:

01-04-2014 | Original Paper

Lymphatic vessels: new targets for the treatment of inflammatory diseases

Authors: Lothar C. Dieterich, Catharina D. Seidel, Michael Detmar

Published in: Angiogenesis | Issue 2/2014

Abstract

The lymphatic system plays an important role in the physiological control of the tissue fluid balance and in the initiation of immune responses. Recent studies have shown that lymphangiogenesis, the growth of new lymphatic vessels and/or the expansion of existing lymphatic vessels, is a characteristic feature of acute inflammatory reactions and of chronic inflammatory diseases. In these conditions, lymphatic vessel expansion occurs at the tissue level but also within the draining lymph nodes. Surprisingly, activation of lymphatic vessel function by delivery of vascular endothelial growth factor-C exerts anti-inflammatory effects in several models of cutaneous and joint inflammation. These effects are likely mediated by enhanced drainage of extravasated fluid and inflammatory cells, but also by lymphatic vessel-mediated modulation of immune responses. Although some of the underlying mechanisms are just beginning to be identified, lymphatic vessels have emerged as important targets for the development of new therapeutic strategies to treat inflammatory conditions. In this context, it is of great interest that some of the currently used anti-inflammatory drugs also potently activate lymphatic vessels.

Albrecht I, Christofori G (2011) Molecular mechanisms of lymphangiogenesis in development and cancer. Int J Dev Biol 55(4–5):483–494. doi:10.1387/ijdb.103226ia PubMedCrossRef

Alitalo K (2011) The lymphatic vasculature in disease. Nat Med 17(11):1371–1380. doi:10.1038/nm.2545 PubMedCrossRef

Cueni LN, Detmar M (2006) New insights into the molecular control of the lymphatic vascular system and its role in disease. J Invest Dermatol 126(10):2167–2177. doi:10.1038/sj.jid.5700464 PubMedCrossRef

Halin C, Detmar M (2008) Chapter 1. Inflammation, angiogenesis, and lymphangiogenesis. Methods Enzymol 445:1–25. doi:10.1016/S0076-6879(08)03001-2 PubMedCrossRef

Hirakawa S, Hong YK, Harvey N, Schacht V, Matsuda K, Libermann T, Detmar M (2003) Identification of vascular lineage-specific genes by transcriptional profiling of isolated blood vascular and lymphatic endothelial cells. Am J Pathol 162(2):575–586. doi:10.1016/S0002-9440(10)63851-5 PubMedCentralPubMedCrossRef

Kriehuber E, Breiteneder-Geleff S, Groeger M, Soleiman A, Schoppmann SF, Stingl G, Kerjaschki D, Maurer D (2001) Isolation and characterization of dermal lymphatic and blood endothelial cells reveal stable and functionally specialized cell lineages. J Exp Med 194(6):797–808PubMedCentralPubMedCrossRef

Petrova TV, Makinen T, Makela TP, Saarela J, Virtanen I, Ferrell RE, Finegold DN, Kerjaschki D, Yla-Herttuala S, Alitalo K (2002) Lymphatic endothelial reprogramming of vascular endothelial cells by the Prox-1 homeobox transcription factor. EMBO J 21(17):4593–4599PubMedCentralPubMedCrossRef

Makinen T, Veikkola T, Mustjoki S, Karpanen T, Catimel B, Nice EC, Wise L, Mercer A, Kowalski H, Kerjaschki D, Stacker SA, Achen MG, Alitalo K (2001) Isolated lymphatic endothelial cells transduce growth, survival and migratory signals via the VEGF-C/D receptor VEGFR-3. EMBO J 20(17):4762–4773. doi:10.1093/emboj/20.17.4762 PubMedCentralPubMedCrossRef

Tammela T, Alitalo K (2010) Lymphangiogenesis: molecular mechanisms and future promise. Cell 140(4):460–476. doi:10.1016/j.cell.2010.01.045 PubMedCrossRef

10.

Kaipainen A, Korhonen J, Mustonen T, van Hinsbergh VW, Fang GH, Dumont D, Breitman M, Alitalo K (1995) Expression of the fms-like tyrosine kinase 4 gene becomes restricted to lymphatic endothelium during development. Proc Natl Acad Sci USA 92(8):3566–3570PubMedCentralPubMedCrossRef

11.

Partanen TA, Arola J, Saaristo A, Jussila L, Ora A, Miettinen M, Stacker SA, Achen MG, Alitalo K (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(13):2087–2096. doi:10.1096/fj.99-1049com PubMedCrossRef

12.

Wigle JT, Oliver G (1999) Prox1 function is required for the development of the murine lymphatic system. Cell 98(6):769–778PubMedCrossRef

13.

Hong YK, Foreman K, Shin JW, Hirakawa S, Curry CL, Sage DR, Libermann T, Dezube BJ, Fingeroth JD, Detmar M (2004) Lymphatic reprogramming of blood vascular endothelium by Kaposi sarcoma-associated herpesvirus. Nat Genet 36(7):683–685PubMedCrossRef

14.

Banerji S, Ni J, Wang SX, Clasper S, Su J, Tammi R, Jones M, Jackson DG (1999) LYVE-1, a new homologue of the CD44 glycoprotein, is a lymph-specific receptor for hyaluronan. J Cell Biol 144(4):789–801PubMedCentralPubMedCrossRef

15.

Gale NW, Prevo R, Espinosa J, Ferguson DJ, Dominguez MG, Yancopoulos GD, Thurston G, Jackson DG (2007) Normal lymphatic development and function in mice deficient for the lymphatic hyaluronan receptor LYVE-1. Mol Cell Biol 27(2):595–604. doi:10.1128/MCB.01503-06 PubMedCentralPubMedCrossRef

16.

Makinen T, Adams RH, Bailey J, Lu Q, Ziemiecki A, Alitalo K, Klein R, Wilkinson GA (2005) PDZ interaction site in ephrinB2 is required for the remodeling of lymphatic vasculature. Genes Dev 19(3):397–410. doi:10.1101/gad.330105 PubMedCentralPubMedCrossRef

17.

Mouta Carreira C, Nasser SM, di Tomaso E, Padera TP, Boucher Y, Tomarev SI, Jain RK (2001) LYVE-1 is not restricted to the lymph vessels: expression in normal liver blood sinusoids and down-regulation in human liver cancer and cirrhosis. Cancer Res 61(22):8079–8084PubMed

18.

Breiteneder-Geleff S, Soleiman A, Kowalski H, Horvat R, Amann G, Kriehuber E, Diem K, Weninger W, Tschachler E, Alitalo K, Kerjaschki D (1999) Angiosarcomas express mixed endothelial phenotypes of blood and lymphatic capillaries: podoplanin as a specific marker for lymphatic endothelium. Am J Pathol 154(2):385–394. doi:10.1016/S0002-9440(10)65285-6 PubMedCentralPubMedCrossRef

19.

Schacht V, Ramirez MI, Hong YK, Hirakawa S, Feng D, Harvey N, Williams M, Dvorak AM, Dvorak HF, Oliver G, Detmar M (2003) T1alpha/podoplanin deficiency disrupts normal lymphatic vasculature formation and causes lymphedema. EMBO J 22(14):3546–3556. doi:10.1093/emboj/cdg342 PubMedCentralPubMedCrossRef

20.

Wick N, Haluza D, Gurnhofer E, Raab I, Kasimir MT, Prinz M, Steiner CW, Reinisch C, Howorka A, Giovanoli P, Buchsbaum S, Krieger S, Tschachler E, Petzelbauer P, Kerjaschki D (2008) Lymphatic precollectors contain a novel, specialized subpopulation of podoplanin low, CCL27-expressing lymphatic endothelial cells. Am J Pathol 173(4):1202–1209. doi:10.2353/ajpath.2008.080101 PubMedCentralPubMedCrossRef

21.

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(1):57–68. doi:10.1016/S0002-9440(10)63630-9 PubMedCentralPubMedCrossRef

22.

Cursiefen C, Chen L, Saint-Geniez M, Hamrah P, Jin Y, Rashid S, Pytowski B, Persaud K, Wu Y, Streilein JW, Dana R (2006) Nonvascular VEGF receptor 3 expression by corneal epithelium maintains avascularity and vision. Proc Natl Acad Sci U S A 103(30):11405–11410. doi:10.1073/pnas.0506112103 PubMedCentralPubMedCrossRef

23.

Burke Z, Oliver G (2002) Prox1 is an early specific marker for the developing liver and pancreas in the mammalian foregut endoderm. Mech Dev 118(1–2):147–155PubMedCrossRef

24.

Lavado A, Oliver G (2007) Prox1 expression patterns in the developing and adult murine brain. Dev Dyn 236(2):518–524. doi:10.1002/dvdy.21024 PubMedCrossRef

25.

Galeeva A, Treuter E, Tomarev S, Pelto-Huikko M (2007) A prospero-related homeobox gene Prox-1 is expressed during postnatal brain development as well as in the adult rodent brain. Neuroscience 146(2):604–616. doi:10.1016/j.neuroscience.2007.02.002 PubMedCrossRef

26.

Chen L, Cursiefen C, Barabino S, Zhang Q, Dana MR (2005) Novel expression and characterization of lymphatic vessel endothelial hyaluronate receptor 1 (LYVE-1) by conjunctival cells. Invest Ophthalmol Vis Sci 46(12):4536–4540. doi:10.1167/iovs.05-0975 PubMedCentralPubMedCrossRef

27.

Cho CH, Koh YJ, Han J, Sung HK, Jong Lee H, Morisada T, Schwendener RA, Brekken RA, Kang G, Oike Y, Choi TS, Suda T, Yoo OJ, Koh GY (2007) Angiogenic role of LYVE-1-positive macrophages in adipose tissue. Circ Res 100(4):e47–e57. doi:10.1161/01.RES.0000259564.92792.93 PubMedCrossRef

28.

Schledzewski K, Falkowski M, Moldenhauer G, Metharom P, Kzhyshkowska J, Ganss R, Demory A, Falkowska-Hansen B, Kurzen H, Ugurel S, Geginat G, Arnold B, Goerdt S (2006) Lymphatic endothelium-specific hyaluronan receptor LYVE-1 is expressed by stabilin-1+, F4/80+, CD11b+ macrophages in malignant tumours and wound healing tissue in vivo and in bone marrow cultures in vitro: implications for the assessment of lymphangiogenesis. J Pathol 209(1):67–77. doi:10.1002/path.1942 PubMedCrossRef

29.

Williams MC, Cao Y, Hinds A, Rishi AK, Wetterwald A (1996) T1 alpha protein is developmentally regulated and expressed by alveolar type I cells, choroid plexus, and ciliary epithelia of adult rats. Am J Respir Cell Mol Biol 14(6):577–585. doi:10.1165/ajrcmb.14.6.8652186 PubMedCrossRef

30.

Kaji C, Tomooka M, Kato Y, Kojima H, Sawa Y (2012) The expression of podoplanin and classic cadherins in the mouse brain. J Anat 220(5):435–446. doi:10.1111/j.1469-7580.2012.01484.x PubMedCrossRef

31.

Ramirez MI, Millien G, Hinds A, Cao Y, Seldin DC, Williams MC (2003) T1alpha, a lung type I cell differentiation gene, is required for normal lung cell proliferation and alveolus formation at birth. Dev Biol 256(1):61–72PubMedCrossRef

32.

Bekiaris V, Withers D, Glanville SH, McConnell FM, Parnell SM, Kim MY, Gaspal FM, Jenkinson E, Sweet C, Anderson G, Lane PJ (2007) Role of CD30 in B/T segregation in the spleen. J Immunol 179(11):7535–7543PubMedCrossRef

33.

Malhotra D, Fletcher AL, Astarita J, Lukacs-Kornek V, Tayalia P, Gonzalez SF, Elpek KG, Chang SK, Knoblich K, Hemler ME, Brenner MB, Carroll MC, Mooney DJ, Turley SJ (2012) Transcriptional profiling of stroma from inflamed and resting lymph nodes defines immunological hallmarks. Nat Immunol 13(5):499–510. doi:10.1038/ni.2262 PubMedCentralPubMedCrossRef

34.

Hou TZ, Bystrom J, Sherlock JP, Qureshi O, Parnell SM, Anderson G, Gilroy DW, Buckley CD (2010) A distinct subset of podoplanin (gp38) expressing F4/80+ macrophages mediate phagocytosis and are induced following zymosan peritonitis. FEBS Lett 584(18):3955–3961. doi:10.1016/j.febslet.2010.07.053 PubMedCrossRef

35.

Kerrigan AM, Navarro-Nunez L, Pyz E, Finney BA, Willment JA, Watson SP, Brown GD (2012) Podoplanin-expressing inflammatory macrophages activate murine platelets via CLEC-2. J Thromb Haemost 10(3):484–486. doi:10.1111/j.1538-7836.2011.04614.x PubMedCentralPubMedCrossRef

36.

Peters A, Pitcher LA, Sullivan JM, Mitsdoerffer M, Acton SE, Franz B, Wucherpfennig K, Turley S, Carroll MC, Sobel RA, Bettelli E, Kuchroo VK (2011) Th17 cells induce ectopic lymphoid follicles in central nervous system tissue inflammation. Immunity 35(6):986–996. doi:10.1016/j.immuni.2011.10.015 PubMedCentralPubMedCrossRef

37.

Fujii T, Zen Y, Sato Y, Sasaki M, Enomae M, Minato H, Masuda S, Uehara T, Katsuyama T, Nakanuma Y (2008) Podoplanin is a useful diagnostic marker for epithelioid hemangioendothelioma of the liver. Mod Pathol 21(2):125–130. doi:10.1038/modpathol.3800986 PubMed

38.

Baluk P, McDonald DM (2008) Markers for microscopic imaging of lymphangiogenesis and angiogenesis. Ann N Y Acad Sci 1131:1–12. doi:10.1196/annals.1413.001 PubMedCrossRef

39.

Clasper S, Royston D, Baban D, Cao Y, Ewers S, Butz S, Vestweber D, Jackson DG (2008) A novel gene expression profile in lymphatics associated with tumor growth and nodal metastasis. Cancer Res 68(18):7293–7303. doi:10.1158/0008-5472.CAN-07-6506 PubMedCrossRef

40.

Groger M, Loewe R, Holnthoner W, Embacher R, Pillinger M, Herron GS, Wolff K, Petzelbauer P (2004) IL-3 induces expression of lymphatic markers Prox-1 and podoplanin in human endothelial cells. J Immunol 173(12):7161–7169PubMedCrossRef

41.

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(2):247–257. doi:10.1172/JCI22037 PubMedCentralPubMedCrossRef

42.

Johnson LA, Prevo R, Clasper S, Jackson DG (2007) Inflammation-induced uptake and degradation of the lymphatic endothelial hyaluronan receptor LYVE-1. J Biol Chem 282(46):33671–33680. doi:10.1074/jbc.M702889200 PubMedCrossRef

43.

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(1):205–215. doi:10.1182/blood-2010-12-326447 PubMedCrossRef

44.

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(17):4667–4678. doi:10.1182/blood-2010-10-316356 PubMedCentralPubMedCrossRef

45.

Flister MJ, Wilber A, Hall KL, Iwata C, Miyazono K, Nisato RE, Pepper MS, Zawieja DC, Ran S (2010) Inflammation induces lymphangiogenesis through up-regulation of VEGFR-3 mediated by NF-kappaB and Prox1. Blood 115(2):418–429. doi:10.1182/blood-2008-12-196840 PubMedCentralPubMedCrossRef

46.

Proulx ST, Luciani P, Dieterich LC, Karaman S, Leroux JC, Detmar M (2013) Expansion of the lymphatic vasculature in cancer and inflammation: new opportunities for in vivo imaging and drug delivery. J Control Release. doi:10.1016/j.jconrel.2013.04.027 PubMed

47.

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(4):1048–1057. doi:10.1182/blood-2003-08-2964 PubMedCrossRef

48.

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. Arthritis Res Ther 9(6):R118. doi:10.1186/ar2326 PubMedCentralPubMedCrossRef

49.

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(12):1227–1229PubMedCentralPubMedCrossRef

50.

Shi J, Liang Q, Wang Y, Mooney R, Boyce B, Xing L (2012) Use of a whole-slide imaging system to assess the presence and alteration of lymphatic vessels in joint sections of arthritic mice. Biotech Histochem. doi:10.3109/10520295.2012.729864 PubMedCentral

51.

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(7):567–579. doi:10.1111/j.1549-8719.2012.00189.x PubMedCrossRef

52.

Alexander JS, Chaitanya GV, Grisham MB, Boktor M (2010) Emerging roles of lymphatics in inflammatory bowel disease. Ann N Y Acad Sci 1207(Suppl 1):E75–E85. doi:10.1111/j.1749-6632.2010.05757.x PubMedCrossRef

53.

Jurisic G, Sundberg JP, Bleich A, Leiter EH, Broman KW, Buechler G, Alley L, Vestweber D, Detmar M (2010) Quantitative lymphatic vessel trait analysis suggests Vcam1 as candidate modifier gene of inflammatory bowel disease. Genes Immun 11(3):219–231. doi:10.1038/gene.2010.4 PubMedCentralPubMedCrossRef

54.

Nagy JA, Vasile E, Feng D, Sundberg C, Brown LF, Detmar MJ, Lawitts JA, Benjamin L, Tan X, Manseau EJ, Dvorak AM, Dvorak HF (2002) Vascular permeability factor/vascular endothelial growth factor induces lymphangiogenesis as well as angiogenesis. J Exp Med 196(11):1497–1506PubMedCentralPubMedCrossRef

55.

Mumprecht V, Roudnicky F, Detmar M (2012) Inflammation-induced lymph node lymphangiogenesis is reversible. Am J Pathol 180(3):874–879. doi:10.1016/j.ajpath.2011.11.010 PubMedCentralPubMedCrossRef

56.

Kelley PM, Conner AL, Tempero RM (2013) Lymphatic vessel memory stimulated by recurrent inflammation. Am J Pathol. doi:10.1016/j.ajpath.2013.02.025

57.

Hirakawa S, Kodama S, Kunstfeld R, Kajiya K, Brown LF, Detmar M (2005) VEGF-A induces tumor and sentinel lymph node lymphangiogenesis and promotes lymphatic metastasis. J Exp Med 201(7):1089–1099. doi:10.1084/jem.20041896 PubMedCentralPubMedCrossRef

58.

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(2):203–215. doi:10.1016/j.immuni.2006.01.003 PubMedCrossRef

59.

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(9):3158–3167. doi:10.1182/blood-2007-01-066811 PubMedCentralPubMedCrossRef

60.

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(22):5650–5659. doi:10.1182/blood-2008-09-176776 PubMedCrossRef

61.

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(1):96–107. doi:10.1016/j.immuni.2010.12.016 PubMedCrossRef

62.

Hong YK, Lange-Asschenfeldt B, Velasco P, Hirakawa S, Kunstfeld R, Brown LF, Bohlen P, Senger DR, Detmar M (2004) VEGF-A promotes tissue repair-associated lymphatic vessel formation via VEGFR-2 and the alpha1beta1 and alpha2beta1 integrins. FASEB J 18(10):1111–1113PubMed

63.

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(10):2255–2269. doi:10.1084/jem.20100559 PubMedCentralPubMedCrossRef

64.

Forsythe JA, Jiang BH, Iyer NV, Agani F, Leung SW, Koos RD, Semenza GL (1996) Activation of vascular endothelial growth factor gene transcription by hypoxia-inducible factor 1. Mol Cell Biol 16(9):4604–4613PubMedCentralPubMed

65.

Gale NW, Thurston G, Hackett SF, Renard R, Wang Q, McClain J, Martin C, Witte C, Witte MH, Jackson D, Suri C, Campochiaro PA, Wiegand SJ, Yancopoulos GD (2002) Angiopoietin-2 is required for postnatal angiogenesis and lymphatic patterning, and only the latter role is rescued by angiopoietin-1. Dev Cell 3(3):411–423PubMedCrossRef

66.

Morisada T, Oike Y, Yamada Y, Urano T, Akao M, Kubota Y, Maekawa H, Kimura Y, Ohmura M, Miyamoto T, Nozawa S, Koh GY, Alitalo K, Suda T (2005) Angiopoietin-1 promotes LYVE-1-positive lymphatic vessel formation. Blood 105(12):4649–4656. doi:10.1182/blood-2004-08-3382 PubMedCrossRef

67.

Chang LK, Garcia-Cardena G, Farnebo F, Fannon M, Chen EJ, Butterfield C, Moses MA, Mulligan RC, Folkman J, Kaipainen A (2004) Dose-dependent response of FGF-2 for lymphangiogenesis. Proc Natl Acad Sci U S A 101(32):11658–11663. doi:10.1073/pnas.0404272101 PubMedCentralPubMedCrossRef

68.

Shin JW, Min M, Larrieu-Lahargue F, Canron X, Kunstfeld R, Nguyen L, Henderson JE, Bikfalvi A, Detmar M, Hong YK (2006) Prox1 promotes lineage-specific expression of fibroblast growth factor (FGF) receptor-3 in lymphatic endothelium: a role for FGF signaling in lymphangiogenesis. Mol Biol Cell 17(2):576–584. doi:10.1091/mbc.E05-04-0368 PubMedCentralPubMedCrossRef

69.

Kajiya K, Hirakawa S, Ma B, Drinnenberg I, Detmar M (2005) Hepatocyte growth factor promotes lymphatic vessel formation and function. EMBO J 24(16):2885–2895. doi:10.1038/sj.emboj.7600763 PubMedCentralPubMedCrossRef

70.

Cao R, Bjorndahl MA, Religa P, Clasper S, Garvin S, Galter D, Meister B, Ikomi F, Tritsaris K, Dissing S, Ohhashi T, Jackson DG, Cao Y (2004) PDGF-BB induces intratumoral lymphangiogenesis and promotes lymphatic metastasis. Cancer Cell 6(4):333–345. doi:10.1016/j.ccr.2004.08.034 PubMedCrossRef

71.

Bjorndahl M, Cao R, Nissen LJ, Clasper S, Johnson LA, Xue Y, Zhou Z, Jackson D, Hansen AJ, Cao Y (2005) Insulin-like growth factors 1 and 2 induce lymphangiogenesis in vivo. Proc Natl Acad Sci U S A 102(43):15593–15598. doi:10.1073/pnas.0507865102 PubMedCentralPubMedCrossRef

72.

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(11):2605–2613. doi:10.1182/blood-2008-07-166934 PubMedCrossRef

73.

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(4):1733–1745. doi:10.2353/ajpath.2009.090133 PubMedCentralPubMedCrossRef

74.

Baluk P, Hogmalm A, Bry M, Alitalo K, Bry K, McDonald DM (2013) Transgenic overexpression of interleukin-1beta induces persistent lymphangiogenesis but not angiogenesis in mouse airways. Am J Pathol 182(4):1434–1447. doi:10.1016/j.ajpath.2012.12.003 PubMedCentralPubMedCrossRef

75.

Watari K, Nakao S, Fotovati A, Basaki Y, Hosoi F, Bereczky B, Higuchi R, Miyamoto T, Kuwano M, Ono M (2008) Role of macrophages in inflammatory lymphangiogenesis: enhanced production of vascular endothelial growth factor C and D through NF-kappaB activation. Biochem Biophys Res Commun 377(3):826–831. doi:10.1016/j.bbrc.2008.10.077 PubMedCrossRef

76.

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(5):1089–1102. doi:10.1084/jem.20081605 PubMedCentralPubMedCrossRef

77.

Cha HS, Bae EK, Koh JH, Chai JY, Jeon CH, Ahn KS, Kim J, Koh EM (2007) Tumor necrosis factor-alpha induces vascular endothelial growth factor-C expression in rheumatoid synoviocytes. J Rheumatol 34(1):16–19PubMed

78.

Chaitanya GV, Franks SE, Cromer W, Wells SR, Bienkowska M, Jennings MH, Ruddell A, Ando T, Wang Y, Gu Y, Sapp M, Mathis JM, Jordan PA, Minagar A, Alexander JS (2010) Differential cytokine responses in human and mouse lymphatic endothelial cells to cytokines in vitro. Lymphat Res Biol 8(3):155–164. doi:10.1089/lrb 2010.0004PubMedCentralPubMedCrossRef

79.

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(4):1496–1503. doi:10.2353/ajpath.2006.060197 PubMedCentralPubMedCrossRef

80.

Zhou Q, Wood R, Schwarz EM, Wang YJ, Xing L (2010) Near-infrared lymphatic imaging demonstrates the dynamics of lymph flow and lymphangiogenesis during the acute versus chronic phases of arthritis in mice. Arthritis Rheum 62(7):1881–1889. doi:10.1002/art.27464 PubMedCentralPubMed

81.

Zhou Q, Guo R, Wood R, Boyce BF, Liang Q, Wang YJ, Schwarz EM, Xing L (2011) Vascular endothelial growth factor C attenuates joint damage in chronic inflammatory arthritis by accelerating local lymphatic drainage in mice. Arthritis Rheum 63(8):2318–2328. doi:10.1002/art.30421 PubMedCentralPubMedCrossRef

82.

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. Arthritis Rheum 60(9):2666–2676. doi:10.1002/art.24764 PubMedCentralPubMedCrossRef

83.

Xia YP, Li B, Hylton D, Detmar M, Yancopoulos GD, Rudge JS (2003) Transgenic delivery of VEGF to mouse skin leads to an inflammatory condition resembling human psoriasis. Blood 102(1):161–168. doi:10.1182/blood-2002-12-3793 PubMedCrossRef

84.

Hirakawa S, Fujii S, Kajiya K, Yano K, Detmar M (2005) Vascular endothelial growth factor promotes sensitivity to ultraviolet B-induced cutaneous photodamage. Blood 105(6):2392–2399. doi:10.1182/blood-2004-06-2435 PubMedCrossRef

85.

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(5):1292–1298. doi:10.1038/jid.2008.351 PubMedCrossRef

86.

Kajiya K, Detmar M (2006) An important role of lymphatic vessels in the control of UVB-induced edema formation and inflammation. J Invest Dermatol 126(4):919–921. doi:10.1038/sj.jid.5700126 PubMedCrossRef

87.

Jurisic G, Sundberg JP, Detmar M (2013) Blockade of VEGF receptor-3 aggravates inflammatory bowel disease and lymphatic vessel enlargement. Inflamm Bowel Dis 19:1983–1989PubMed

88.

Tewalt EF, Cohen JN, Rouhani SJ, Engelhard VH (2012) Lymphatic endothelial cells—key players in regulation of tolerance and immunity. Front Immunol 3:305. doi:10.3389/fimmu.2012.00305 PubMedCentralPubMedCrossRef

89.

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. doi:10.1182/blood-2012-04-425314 PubMed

90.

Vetrano S, Borroni EM, Sarukhan A, Savino B, Bonecchi R, Correale C, Arena V, Fantini M, Roncalli M, Malesci A, Mantovani A, Locati M, Danese S (2010) The lymphatic system controls intestinal inflammation and inflammation-associated colon cancer through the chemokine decoy receptor D6. Gut 59(2):197–206. doi:10.1136/gut.2009.183772 PubMedCrossRef

91.

Cyster JG, Schwab SR (2012) Sphingosine-1-phosphate and lymphocyte egress from lymphoid organs. Annu Rev Immunol 30:69–94. doi:10.1146/annurev-immunol-020711-075011 PubMedCrossRef

92.

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(8):4065–4080. doi:10.4049/jimmunol.1101854 PubMedCrossRef

93.

Khan O, Headley M, Gerard A, Wei W, Liu L, Krummel MF (2011) Regulation of T cell priming by lymphoid stroma. PLoS ONE 6(11):e26138. doi:10.1371/journal.pone.0026138 PubMedCentralPubMedCrossRef

94.

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(11):1096–1104. doi:10.1038/ni.2112 PubMedCentralPubMedCrossRef

95.

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(3):1767–1779. doi:10.4049/jimmunol.0802167 PubMedCrossRef

96.

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(4):681–688. doi:10.1084/jem.20092465 PubMedCentralPubMedCrossRef

97.

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(4):689–697. doi:10.1084/jem.20092642 PubMedCentralPubMedCrossRef

98.

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(24):4772–4782. doi:10.1182/blood-2012-04-427013 PubMedCentralPubMedCrossRef

99.

Alitalo A, Detmar M (2012) Interaction of tumor cells and lymphatic vessels in cancer progression. Oncogene 31(42):4499–4508. doi:10.1038/onc.2011.602 PubMedCrossRef

100.

Shimizu Y, Shibata R, Shintani S, Ishii M, Murohara T (2012) Therapeutic lymphangiogenesis with implantation of adipose-derived regenerative cells. J Am Heart Assoc 1(4):e000877. doi:10.1161/JAHA.112.000877 PubMedCentralPubMedCrossRef

101.

Choi I, Lee YS, Chung HK, Choi D, Ecoiffier T, Lee HN, Kim KE, Lee S, Park EK, Maeng YS, Kim NY, Ladner RD, Petasis NA, Koh CJ, Chen L, Lenz HJ, Hong YK (2013) Interleukin-8 reduces post-surgical lymphedema formation by promoting lymphatic vessel regeneration. Angiogenesis 16(1):29–44. doi:10.1007/s10456-012-9297-6 PubMedCrossRef

102.

Choi I, Lee S, Kyoung Chung H, Suk Lee Y, Eui Kim K, Choi D, Park EK, Yang D, Ecoiffier T, Monahan J, Chen W, Aguilar B, Lee HN, Yoo J, Koh CJ, Chen L, Wong AK, Hong YK (2012) 9-cis retinoic acid promotes lymphangiogenesis and enhances lymphatic vessel regeneration: therapeutic implications of 9-cis retinoic acid for secondary lymphedema. Circulation 125(7):872–882. doi:10.1161/CIRCULATIONAHA.111.030296 PubMedCentralPubMedCrossRef

103.

Marino D, Dabouras V, Brändli AW, Detmar M (2011) A role for all-trans-retinoic acid in the early steps of lymphatic vasculature development. J Vasc Res 48:236–251PubMedCentralPubMedCrossRef

104.

Iwata C, Kano MR, Komuro A, Oka M, Kiyono K, Johansson E, Morishita Y, Yashiro M, Hirakawa K, Kaminishi M, Miyazono K (2007) Inhibition of cyclooxygenase-2 suppresses lymph node metastasis via reduction of lymphangiogenesis. Cancer Res 67(21):10181–10189. doi:10.1158/0008-5472.CAN-07-2366 PubMedCrossRef

105.

Kashiwagi S, Hosono K, Suzuki T, Takeda A, Uchinuma E, Majima M (2011) Role of COX-2 in lymphangiogenesis and restoration of lymphatic flow in secondary lymphedema. Lab Invest 91(9):1314–1325. doi:10.1038/labinvest.2011.84 PubMedCrossRef

106.

Karnezis T, Shayan R, Caesar C, Roufail S, Harris NC, Ardipradja K, Zhang YF, Williams SP, Farnsworth RH, Chai MG, Rupasinghe TW, Tull DL, Baldwin ME, Sloan EK, Fox SB, Achen MG, Stacker SA (2012) VEGF-D promotes tumor metastasis by regulating prostaglandins produced by the collecting lymphatic endothelium. Cancer Cell 21(2):181–195. doi:10.1016/j.ccr.2011.12.026 PubMedCrossRef

107.

Yao LC, Baluk P, Feng J, McDonald DM (2010) Steroid-resistant lymphatic remodeling in chronically inflamed mouse airways. Am J Pathol 176(3):1525–1541. doi:10.2353/ajpath.2010.090909 PubMedCentralPubMedCrossRef

108.

Steele MM, Kelley PM, Schieler AM, Tempero RM (2011) Glucocorticoids suppress corneal lymphangiogenesis. Cornea 30(12):1442–1447. doi:10.1097/ICO.0b013e318213f39f PubMedCrossRef

109.

Hos D, Saban DR, Bock F, Regenfuss B, Onderka J, Masli S, Cursiefen C (2011) Suppression of inflammatory corneal lymphangiogenesis by application of topical corticosteroids. Arch Ophthalmol 129(4):445–452. doi:10.1001/archophthalmol.2011.42 PubMedCrossRef

110.

Yano A, Fujii Y, Iwai A, Kawakami S, Kageyama Y, Kihara K (2006) Glucocorticoids suppress tumor lymphangiogenesis of prostate cancer cells. Clin Cancer Res 12(20 Pt 1):6012–6017. doi:10.1158/1078-0432.CCR-06-0749 PubMedCrossRef

111.

Okanobo A, Chauhan SK, Dastjerdi MH, Kodati S, Dana R (2012) Efficacy of topical blockade of interleukin-1 in experimental dry eye disease. Am J Ophthalmol 154(1):63–71. doi:10.1016/j.ajo.2012.01.034 PubMedCentralPubMedCrossRef

112.

Shinriki S, Jono H, Ueda M, Ota K, Ota T, Sueyoshi T, Oike Y, Ibusuki M, Hiraki A, Nakayama H, Shinohara M, Ando Y (2011) Interleukin-6 signalling regulates vascular endothelial growth factor-C synthesis and lymphangiogenesis in human oral squamous cell carcinoma. J Pathol 225(1):142–150. doi:10.1002/path.2935 PubMedCrossRef

113.

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(11):1610–1616. doi:10.1136/ard.2007.083394 PubMedCrossRef

114.

Schulz MM, Reisen F, Zgraggen S, Fischer S, Yuen D, Kang GJ, Chen L, Schneider G, Detmar M (2012) Phenotype-based high-content chemical library screening identifies statins as inhibitors of in vivo lymphangiogenesis. Proc Natl Acad Sci U S A 109(40):E2665–E2674. doi:10.1073/pnas.1206036109 PubMedCentralPubMedCrossRef

115.

Baluk P, Yao LC, Feng J, Romano T, Jung SS, Schreiter JL, Yan L, Shealy DJ, McDonald DM (2009) TNF-alpha drives remodeling of blood vessels and lymphatics in sustained airway inflammation in mice. J Clin Invest 119(10):2954–2964. doi:10.1172/JCI37626 PubMedCentralPubMed

116.

Fiorentini S, Luganini A, Dell’Oste V, Lorusso B, Cervi E, Caccuri F, Bonardelli S, Landolfo S, Caruso A, Gribaudo G (2011) Human cytomegalovirus productively infects lymphatic endothelial cells and induces a secretome that promotes angiogenesis and lymphangiogenesis through interleukin-6 and granulocyte-macrophage colony-stimulating factor. J Gen Virol 92(Pt 3):650–660. doi:10.1099/vir.0.025395-0 PubMedCrossRef

117.

Chen X, Xie Q, Cheng X, Diao X, Cheng Y, Liu J, Xie W, Chen Z, Zhu B (2010) Role of interleukin-17 in lymphangiogenesis in non-small-cell lung cancer: enhanced production of vascular endothelial growth factor C in non-small-cell lung carcinoma cells. Cancer Sci 101(11):2384–2390. doi:10.1111/j.1349-7006.2010.01684.x PubMedCrossRef

118.

Chauhan SK, Jin Y, Goyal S, Lee HS, Fuchsluger TA, Lee HK, Dana R (2011) A novel pro-lymphangiogenic function for Th17/IL-17. Blood 118(17):4630–4634. doi:10.1182/blood-2011-01-332049 PubMedCentralPubMedCrossRef

119.

Yamashita M, Iwama N, Date F, Shibata N, Miki H, Yamauchi K, Sawai T, Sato S, Takahashi T, Ono M (2009) Macrophages participate in lymphangiogenesis in idiopathic diffuse alveolar damage through CCL19-CCR7 signal. Hum Pathol 40(11):1553–1563. doi:10.1016/j.humpath.2009.03.021 PubMedCrossRef

120.

Zhuo W, Jia L, Song N, Lu XA, Ding Y, Wang X, Song X, Fu Y, Luo Y (2012) The CXCL12-CXCR4 chemokine pathway: a novel axis regulates lymphangiogenesis. Clin Cancer Res 18(19):5387–5398. doi:10.1158/1078-0432.CCR-12-0708 PubMedCrossRef

121.

Su JL, Shih JY, Yen ML, Jeng YM, Chang CC, Hsieh CY, Wei LH, Yang PC, Kuo ML (2004) Cyclooxygenase-2 induces EP1- and HER-2/Neu-dependent vascular endothelial growth factor-C up-regulation: a novel mechanism of lymphangiogenesis in lung adenocarcinoma. Cancer Res 64(2):554–564PubMedCrossRef

122.

Hosono K, Suzuki T, Tamaki H, Sakagami H, Hayashi I, Narumiya S, Alitalo K, Majima M (2011) Roles of prostaglandin E2-EP3/EP4 receptor signaling in the enhancement of lymphangiogenesis during fibroblast growth factor-2-induced granulation formation. Arterioscler Thromb Vasc Biol 31(5):1049–1058. doi:10.1161/ATVBAHA.110.222356 PubMedCrossRef

123.

Kajiya K, Huggenberger R, Drinnenberg I, Ma B, Detmar M (2008) Nitric oxide mediates lymphatic vessel activation via soluble guanylate cyclase alpha1beta1-impact on inflammation. FASEB J 22(2):530–537. doi:10.1096/fj.07-8873com PubMedCrossRef

124.

Lahdenranta J, Hagendoorn J, Padera TP, Hoshida T, Nelson G, Kashiwagi S, Jain RK, Fukumura D (2009) Endothelial nitric oxide synthase mediates lymphangiogenesis and lymphatic metastasis. Cancer Res 69(7):2801–2808. doi:10.1158/0008-5472.CAN-08-4051 PubMedCentralPubMedCrossRef

Title: Lymphatic vessels: new targets for the treatment of inflammatory diseases
Authors: Lothar C. Dieterich
Catharina D. Seidel
Michael Detmar
Publication date: 01-04-2014
Publisher: Springer Netherlands
Published in: Angiogenesis / Issue 2/2014
Print ISSN: 0969-6970
Electronic ISSN: 1573-7209
DOI: https://doi.org/10.1007/s10456-013-9406-1

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