Inflammation and Lymphatic Function

Simon Schwager, Michael Detmar, Simon Schwager, Michael Detmar

Abstract

The lymphatic vasculature plays a crucial role in regulating the inflammatory response by influencing drainage of extravasated fluid, inflammatory mediators, and leukocytes. Lymphatic vessels undergo pronounced enlargement in inflamed tissue and display increased leakiness, indicating reduced functionality. Interfering with lymphatic expansion by blocking the vascular endothelial growth factor C (VEGF-C)/vascular endothelial growth factor receptor 3 (VEGFR-3) signaling axis exacerbates inflammation in a variety of disease models, including inflammatory bowel disease (IBD), rheumatoid arthritis and skin inflammation. In contrast, stimulation of the lymphatic vasculature, e.g., by transgenic or viral overexpression as well as local injections of VEGF-C, has been shown to reduce inflammation severity in models of rheumatoid arthritis, skin inflammation, and IBD. Strikingly, the induced expansion of the lymphatic vasculature improves lymphatic function as assessed by the drainage of dyes, fluorescent tracers or inflammatory cells and labeled antigens. The drainage performance of lymphatic vessels is influenced by vascular permeability and pumping activity, which are influenced by VEGF-C/VEGFR-3 signaling as well as several inflammatory mediators, including TNF-α, IL-1β, and nitric oxide. Considering the beneficial effects of lymphatic activation in inflammation, administration of pro-lymphangiogenic factors like VEGF-C, preferably in a targeted, inflammation site-specific fashion, represents a promising therapeutic approach in the setting of inflammatory pathologies.

Keywords: arthritis; inflammation; inflammatory bowel disease; inflammatory mediators; lymphangiogenesis; lymphatic vessels; psoriasis; skin.

Figures

Figure 1
Figure 1
Effects of lymphatic vessel stimulation or inhibition on skin inflammation. Inflamed skin presents with epidermal thickening, edema and infiltration by inflammatory leukocytes (e.g., CD8-positive cells or macrophages and granulocytes). Stimulation of the lymphatic vasculature alleviates inflammation, reducing edema, epidermal thickening and inflammatory infiltration while improving lymphatic drainage, thus lowering the numbers of inflammatory cells in the inflamed skin. Inhibition of the lymphatic vasculature aggravates inflammation and reduces lymphatic clearance.

References

    1. Kajiya K, Hirakawa S, Detmar M. Vascular endothelial growth factor-A mediates ultraviolet B-induced impairment of lymphatic vessel function. Am J Pathol. (2006) 169:1496–503. 10.2353/ajpath.2006.060197
    1. Chidlow JH, Langston W, Greer JJM, Ostanin D, Abdelbaqi M, Houghton J, et al. . Differential angiogenic regulation of experimental colitis. Am J Pathol. (2006) 169:2014–30. 10.2353/ajpath.2006.051021
    1. Elshabrawy HA, Chen Z, Volin MV, Ravella S, Virupannavar S, Shahrara S. The pathogenic role of angiogenesis in rheumatoid arthritis. Angiogenesis (2015) 18:433–48. 10.1007/s10456-015-9477-2
    1. Skobe M, Detmar M. Structure, function, and molecular control of the skin lymphatic system. J Investig Dermatol Symp Proc. (2000) 5:14–9. 10.1046/j.1087-0024.2000.00001.x
    1. Kaipainen A, Korhonen J, Mustonen T, van Hinsbergh VW, Fang GH, Dumont D, et al. . Expression of the fms-like tyrosine kinase 4 gene becomes restricted to lymphatic endothelium during development. Proc Natl Acad Sci USA. (1995) 92:3566–70. 10.1073/pnas.92.8.3566
    1. Joukov V, Pajusola K, Kaipainen A, Chilov D, Lahtinen I, Kukk E, et al. A novel vascular endothelial growth factor, VEGF-C, is a ligand for the Flt4 (VEGFR-3) and KDR (VEGFR-2) receptor tyrosine kinases. EMBO J. (1996) 15:1751 10.1002/j.1460-2075.1996.tb00359.x
    1. Makinen T, Veikkola T, Mustjoki S, Karpanen T, Catimel B, Nice EC, et al. . Isolated lymphatic endothelial cells transduce growth, survival and migratory signals via the VEGF-C/D receptor VEGFR-3. EMBO J. (2001) 20:4762–73. 10.1093/emboj/20.17.4762
    1. Joukov V, Sorsa T, Kumar V, Jeltsch M, Claesson-Welsh L, Cao Y, et al. . Proteolytic processing regulates receptor specificity and activity of VEGF-C. Embo J. (1997) 16:3898–911. 10.1093/emboj/16.13.3898
    1. Joukov V, Kumar V, Sorsa T, Arighi E, Weich H, Saksela O, et al. . 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. (1998) 273:6599–602. 10.1074/jbc.273.12.6599
    1. Achen MG, Jeltsch M, Kukk E, Makinen T, Vitali A, Wilks AF, et al. . Vascular endothelial growth factor D (VEGF-D) is a ligand for the tyrosine kinases VEGF receptor 2 (Flk1) and VEGF receptor 3 (Flt4). Proc Natl Acad Sci USA. (1998) 95:548–53. 10.1073/pnas.95.2.548
    1. Baldwin ME, Catimel B, Nice EC, Roufail S, Hall NE, Stenvers KL, et al. . The specificity of receptor binding by vascular endothelial growth factor-d is different in mouse and man. J Biol Chem. (2001) 276:19166–71. 10.1074/jbc.M100097200
    1. Jeltsch M, Kaipainen A, Joukov V, Meng X, Lakso M, Rauvala H, et al. . Hyperplasia of lymphatic vessels in VEGF-C transgenic mice. Science (1997) 276:1423–5. 10.1126/science.276.5317.1423
    1. Veikkola T, Jussila L, Makinen T, Karpanen T, Jeltsch M, Petrova TV, et al. . Signalling via vascular endothelial growth factor receptor-3 is sufficient for lymphangiogenesis in transgenic mice. Embo J. (2001) 20:1223–31. 10.1093/emboj/20.6.1223
    1. Makinen T, Jussila L, Veikkola T, Karpanen T, Kettunen MI, Pulkkanen KJ, et al. . Inhibition of lymphangiogenesis with resulting lymphedema in transgenic mice expressing soluble VEGF receptor-3. Nat Med. (2001) 7:199–205. 10.1038/84651
    1. Chaitanya GV, Franks SE, Cromer W, Wells SR, Bienkowska M, Jennings MH, et al. . Differential cytokine responses in human and mouse lymphatic endothelial cells to cytokines in vitro. Lymphat Res Biol. (2010) 8:155–64. 10.1089/lrb.2010.0004
    1. Breslin JW, Yuan SY, Wu MH. VEGF-C alters barrier function of cultured lymphatic endothelial cells through a VEGFR-3-dependent mechanism. Lymphat Res Biol. (2007) 5:105–13. 10.1089/lrb.2007.1004
    1. Breslin JW. ROCK and cAMP promote lymphatic endothelial cell barrier integrity and modulate histamine and thrombin-induced barrier dysfunction. Lymphat Res Biol. (2011) 9:3–11. 10.1089/lrb.2010.0016
    1. Kurtz KH, Moor AN, Souza-Smith FM, Breslin JW. Involvement of H1 and H2 receptors and soluble guanylate cyclase in histamine-induced relaxation of rat mesenteric collecting lymphatics. Microcirculation (2014) 21:593–605. 10.1111/micc.12138
    1. Nizamutdinova IT, Maejima D, Nagai T, Bridenbaugh E, Thangaswamy S, Chatterjee V, et al. . Involvement of histamine in endothelium-dependent relaxation of mesenteric lymphatic vessels. Microcirculation (2014) 21:640–8. 10.1111/micc.12143
    1. Gasheva OY, Zawieja DC, Gashev AA. Contraction-initiated NO-dependent lymphatic relaxation: a self-regulatory mechanism in rat thoracic duct. J Physiol. (2006) 575:821–32. 10.1113/jphysiol.2006.115212
    1. Breslin JW, Gaudreault N, Watson KD, Reynoso R, Yuan SY, Wu MH. Vascular endothelial growth factor-C stimulates the lymphatic pump by a VEGF receptor-3-dependent mechanism. Am J Physiol Heart Circ Physiol. (2007) 293:H709–H718. 10.1152/ajpheart.00102.2007
    1. Liao S, Cheng G, Conner DA, Huang Y, Kucherlapati RS, Munn LL, et al. . Impaired lymphatic contraction associated with immunosuppression. Proc Natl Acad Sci USA. (2011) 108:18784–9. 10.1073/pnas.1116152108
    1. Braverman IM. Electron microscopic studies of the microcirculation in psoriasis. J Invest Dermatol. (1972) 59:91–8. 10.1111/1523-1747.ep12625852
    1. Kunstfeld R. Induction of cutaneous delayed-type hypersensitivity reactions in VEGF-A transgenic mice results in chronic skin inflammation associated with persistent lymphatic hyperplasia. Blood (2004) 104:1048–57. 10.1182/blood-2003-08-2964
    1. Henno A, Blacher S, Lambert C, Colige A, Seidel L, Noël A, et al. . Altered expression of angiogenesis and lymphangiogenesis markers in the uninvolved skin of plaque-type psoriasis. Br J Dermatol. (2009) 160:581–90. 10.1111/j.1365-2133.2008.08889.x
    1. Xia Y-P, Li B, Hylton D, Detmar M, Yancopoulos GD, Rudge JS. Transgenic delivery of VEGF to mouse skin leads to an inflammatory condition resembling human psoriasis. Blood (2003) 102:161–8. 10.1182/blood-2002-12-3793
    1. van der Fits L, Mourits S, Voerman JSA, Kant M, Boon L, Laman JD, et al. . Imiquimod-induced psoriasis-like skin inflammation in mice is mediated via the IL-23/IL-17 axis. J Immunol. (2009) 182:5836–45. 10.4049/jimmunol.0802999
    1. Huggenberger R, Ullmann S, Proulx ST, Pytowski B, Alitalo K, Detmar M. Stimulation of lymphangiogenesis via VEGFR-3 inhibits chronic skin inflammation. J Exp Med. (2010) 207:2255–69. 10.1084/jem.20100559
    1. Kataru RP, Jung K, Jang C, Yang H, Schwendener RA, Baik JE, et al. . Critical role of CD11b+ macrophages and VEGF in inflammatory lymphangiogenesis, antigen clearance, and inflammation resolution. Blood (2009) 113:5650–9. 10.1182/blood-2008-09-176776
    1. Christiansen AJ, Dieterich LC, Ohs I, Bachmann SB, Bianchi R, Proulx ST, et al. . Lymphatic endothelial cells attenuate inflammation via suppression of dendritic cell maturation. Oncotarget (2016) 7:39421–35. 10.18632/oncotarget.9820
    1. Huggenberger R, Siddiqui SS, Brander D, Ullmann S, Zimmermann K, Antsiferova M, et al. . An important role of lymphatic vessel activation in limiting acute inflammation. Blood (2011) 117:4667–78. 10.1182/blood-2010-10-316356
    1. Kajiya K, Sawane M, Huggenberger R, Detmar M. Activation of the VEGFR-3 pathway by VEGF-C attenuates UVB-induced edema formation and skin inflammation by promoting lymphangiogenesis. J Invest Dermatol. (2009) 129:1292–8. 10.1038/jid.2008.351
    1. D'Alessio S, Correale C, Tacconi C, Gandelli A, Pietrogrande G, Vetrano S, et al. . VEGF-C–dependent stimulation of lymphatic function ameliorates experimental inflammatory bowel disease. J Clin Invest. (2014) 124:3863–78. 10.1172/JCI72189
    1. Zhou Q, Guo R, Wood R, Boyce BF, Liang Q, Wang Y-J, et al. . Vascular endothelial growth factor C attenuates joint damage in chronic inflammatory arthritis by accelerating local lymphatic drainage in mice. Arthritis Rheum. (2011) 63:2318–28. 10.1002/art.30421
    1. Liang Q, Ju Y, Chen Y, Wang W, Li J, Zhang L, et al. . Lymphatic endothelial cells efferent to inflamed joints produce iNOS and inhibit lymphatic vessel contraction and drainage in TNF-induced arthritis in mice. Arthritis Res Ther. (2016) 18:62. 10.1186/s13075-016-0963-8
    1. Kajiya K, Detmar M. An important role of lymphatic vessels in the control of UVB-induced edema formation and inflammation. J Invest Dermatol. (2006) 126:919–21. 10.1038/sj.jid.5700126
    1. Jurisic G, Sundberg JP, Detmar M. Blockade of VEGF receptor-3 aggravates inflammatory bowel disease and lymphatic vessel enlargement. Inflamm Bowel Dis. (2013) 19:1983–9. 10.1097/MIB.0b013e31829292f7
    1. Guo R, Zhou Q, Proulx ST, Wood R, Ji R-C, Ritchlin CT, et al. . 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. (2009) 60:2666–76. 10.1002/art.24764
    1. Scaldaferri F, Vetrano S, Sans M, Arena V, Straface G, Stigliano E, et al. . VEGF-A links angiogenesis and inflammation in inflammatory bowel disease pathogenesis. Gastroenterology (2009) 136:585–95.e585. 10.1053/j.gastro.2008.09.064
    1. Chidlow JH, Glawe JD, Pattillo CB, Pardue S, Zhang S, Kevil CG. VEGF164 isoform specific regulation of T-cell-dependent experimental colitis in mice. Inflamm Bowel Dis. (2011) 17:1501–12. 10.1002/ibd.21525
    1. Geleff S, Schoppmann SF, Oberhuber G. Increase in podoplanin-expressing intestinal lymphatic vessels in inflammatory bowel disease. Virchows Arch. (2003) 442:231–7. 10.1007/s00428-002-0744-4
    1. Pedica F, Ligorio C, Tonelli P, Bartolini S, Baccarini P. Lymphangiogenesis in Crohn's disease: an immunohistochemical study using monoclonal antibody D2-40. Virchows Arch. (2008) 452:57–63. 10.1007/s00428-007-0540-2
    1. Heatley RV, Bolton PM, Hughes LE, Owen EW. Mesenteric lymphatic obstruction in Crohn's disease. Digestion (1980) 20:307–13. 10.1159/000198452
    1. Van Kruiningen HJ, Hayes AW, Colombel JF. Granulomas obstruct lymphatics in all layers of the intestine in Crohn's disease. Apmis (2014) 122:1125–9. 10.1111/apm.12268
    1. Crohn BB, Ginzburg L, Oppenheimer GD. Regional ileitis: a pathologic and clinical entity. JAMA (1932) 99:1323–9. 10.1001/jama.1932.02740680019005
    1. Tonelli F, Giudici F, Liscia G. Is lymphatic status related to regression of inflammation in Crohn's disease? World J Gastrointest Surg. (2012) 4:228–33. 10.4240/wjgs.v4.i10.228
    1. Rahier J-F, Dubuquoy L, Colombel J-F, Jouret-Mourin A, Delos M, Ferrante M, et al. . Decreased lymphatic vessel density is associated with postoperative endoscopic recurrence in Crohn's disease. Inflamm Bowel Dis. (2013) 19:2084–90. 10.1097/MIB.0b013e3182971cec
    1. Kühn R, Löhler J, Rennick D, Rajewsky K, Müller W. Interleukin-10-deficient mice develop chronic enterocolitis. Cell (1993) 75:263–74.
    1. Spencer DM, Veldman GM, Banerjee S, Willis J, Levine AD. Distinct inflammatory mechanisms mediate early versus late colitis in mice. Gastroenterology (2002) 122:94–105. 10.1053/gast.2002.30308
    1. Okayasu I, Hatakeyama S, Yamada M, Ohkusa T, Inagaki Y, Nakaya R. A novel method in the induction of reliable experimental acute and chronic ulcerative colitis in mice. Gastroenterology (1990) 98:694–702. 10.1016/0016-5085(90)90290-H
    1. Chassaing B, Aitken JD, Malleshappa M, Vijay-Kumar M. Dextran sulfate sodium (DSS)-induced colitis in mice. Curr Protoc Immunol. (2014) 104:Unit15.25.−15.25.14. 10.1002/0471142735.im1525s104
    1. Vyas SP, Goswami R. A Decade of Th9 Cells: Role of Th9 Cells in Inflammatory Bowel Disease. Front Immunol (2018) 9:1139. 10.3389/fimmu.2018.01139
    1. Wang X, Zhao J, Qin L. VEGF-C mediated enhancement of lymphatic drainage reduces intestinal inflammation by regulating IL-9/IL-17 balance and improving gut microbiota in experimental chronic colitis. Am J Transl Res. (2017) 9:4772–84. Available online at:
    1. Firestein GS. Evolving concepts of rheumatoid arthritis. Nature (2003) 423:356–61. 10.1038/nature01661
    1. Jayson MI, Cavill I, Barks JS. Lymphatic clearance rates in rheumatoid arthritis. Ann Rheum Dis. (1971) 30:638–9. 10.1136/ard.30.6.638
    1. Xu H, Edwards J, Banerji S, Prevo R, Jackson DG, Athanasou NA. Distribution of lymphatic vessels in normal and arthritic human synovial tissues. Ann Rheum Dis. (2003) 62:1227–9. 10.1136/ard.2003.005876
    1. Zhang Q, Lu Y, Proulx ST, Guo R, Yao Z, Schwarz EM, et al. . Increased lymphangiogenesis in joints of mice with inflammatory arthritis. Arthritis Res Ther. (2007) 9:R118. 10.1186/ar2326
    1. Keffer J, Probert L, Cazlaris H, Georgopoulos S, Kaslaris E, Kioussis D, et al. . Transgenic mice expressing human tumour necrosis factor: a predictive genetic model of arthritis. Embo J. (1991) 10:4025–31. 10.1002/j.1460-2075.1991.tb04978.x
    1. Kouskoff V, Korganow AS, Duchatelle V, Degott C, Benoist C, Mathis D. Organ-specific disease provoked by systemic autoimmunity. Cell (1996) 87:811–22. 10.1016/S0092-8674(00)81989-3
    1. Bouta EM, Bell RD, Rahimi H, Xing L, Wood RW, Bingham CO, et al. . Targeting lymphatic function as a novel therapeutic intervention for rheumatoid arthritis. Nat Rev Rheumatol. (2018) 14:94–106. 10.1038/nrrheum.2017.205
    1. Proulx ST, Kwok E, You Z, Beck CA, Shealy DJ, Ritchlin CT, et al. . MRI and quantification of draining lymph node function in inflammatory arthritis. Ann NY Acad Sci USA. (2007) 1117:106–23. 10.1196/annals.1402.016
    1. Zhou Q, Wood R, Schwarz EM, Wang Y-J, Xing L. Near-infrared lymphatic imaging demonstrates the dynamics of lymph flow and lymphangiogenesis during the acute versus chronic phases of arthritis in mice. Arthritis Rheum. (2010) 62:1881–9. 10.1002/art.27464
    1. Proulx ST, Kwok E, You Z, Papuga MO, Beck CA, Shealy DJ, et al. . Longitudinal assessment of synovial, lymph node, and bone volumes in inflammatory arthritis in mice by in vivo magnetic resonance imaging and microfocal computed tomography. Arthritis Rheum. (2007b) 56:4024–37. 10.1002/art.23128
    1. Bouta EM, Ju Y, Rahimi H, de Mesy-Bentley KL, Wood RW, Xing L, et al. . Power Doppler ultrasound phenotyping of expanding versus collapsed popliteal lymph nodes in murine inflammatory arthritis. PLoS ONE (2013) 8:e73766. 10.1371/journal.pone.0073766
    1. Bouta EM, Wood RW, Brown EB, Rahimi H, Ritchlin CT, Schwarz EM. In vivo quantification of lymph viscosity and pressure in lymphatic vessels and draining lymph nodes of arthritic joints in mice. J Physiol. (2014) 592:1213–23. 10.1113/jphysiol.2013.266700
    1. Bouta EM, Kuzin I, de Mesy Bentley K, Wood RW, Rahimi H, Ji R-C, et al. . Brief report: treatment of tumor necrosis factor-transgenic mice with anti-tumor necrosis factor restores lymphatic contractions, repairs lymphatic vessels, and may increase monocyte/macrophage egress. Arthr Rheumatol. (2017) 69:1187–93. 10.1002/art.40047
    1. Manzo A, Caporali R, Vitolo B, Alessi S, Benaglio F, Todoerti M, et al. . Subclinical remodelling of draining lymph node structure in early and established rheumatoid arthritis assessed by power Doppler ultrasonography. Rheumatology (2011) 50:1395–400. 10.1093/rheumatology/ker076
    1. Víteček J, Lojek A, Valacchi G, Kubala L. Arginine-based inhibitors of nitric oxide synthase: therapeutic potential and challenges. Mediators Inflamm. (2012) 2012:318087–22. 10.1155/2012/318087
    1. Detmar M, Brown LF, Claffey KP, Yeo KT, Kocher O, Jackman RW, et al. . Overexpression of vascular permeability factor/vascular endothelial growth factor and its receptors in psoriasis. J Exp Med. (1994) 180:1141–6. 10.1084/jem.180.3.1141
    1. Kim KE, Koh Y-J, Jeon B-H, Jang C, Han J, Kataru RP, et al. . Role of CD11b+ macrophages in intraperitoneal lipopolysaccharide-induced aberrant lymphangiogenesis and lymphatic function in the diaphragm. Am J Pathol. (2009) 175:1733–45. 10.2353/ajpath.2009.090133
    1. Cursiefen C, Chen L, Borges LP, Jackson D, Cao J, Radziejewski C, et al. . VEGF-A stimulates lymphangiogenesis and hemangiogenesis in inflammatory neovascularization via macrophage recruitment. J Clin Invest (2004) 113:1040–50. 10.1172/JCI20465
    1. Ristimäki A, Narko K, Enholm B, Joukov V, Alitalo K. Proinflammatory cytokines regulate expression of the lymphatic endothelial mitogen vascular endothelial growth factor-C. J Biol Chem. (1998) 273:8413–8.
    1. Su J-L, Shih J-Y, Yen M-L, Jeng Y-M, Chang C-C, Hsieh C-Y, et al. . 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. (2004) 64:554–64. 10.1158/0008-5472.CAN-03-1301
    1. Cha H-S, Bae E-K, Koh J-H, Chai J-Y, Jeon CH, Ahn K-S, et al. . Tumor necrosis factor-alpha induces vascular endothelial growth factor-C expression in rheumatoid synoviocytes. J Rheumatol. (2007) 34:16–9. Available online at:
    1. Chauhan SK, Jin Y, Goyal S, Lee HS, Fuchsluger TA, Lee HK, et al. . A novel pro-lymphangiogenic function for Th17/IL-17. Blood (2011) 118:4630–4. 10.1182/blood-2011-01-332049
    1. Choi I, Lee YS, Chung HK, Choi D, Ecoiffier T, Lee HN, et al. . Interleukin-8 reduces post-surgical lymphedema formation by promoting lymphatic vessel regeneration. Angiogenesis (2013) 16:29–44. 10.1007/s10456-012-9297-6
    1. Oka M, Iwata C, Suzuki HI, Kiyono K, Morishita Y, Watabe T, et al. . Inhibition of endogenous TGF-beta signaling enhances lymphangiogenesis. Blood (2008) 111:4571–9. 10.1182/blood-2007-10-120337
    1. Avraham T, Daluvoy S, Zampell J, Yan A, Haviv YS, Rockson SG, et al. . Blockade of transforming growth factor-beta1 accelerates lymphatic regeneration during wound repair. Am J Pathol. (2010) 177:3202–14. 10.2353/ajpath.2010.100594
    1. Savetsky IL, Ghanta S, Gardenier JC, Torrisi JS, García Nores GD, Hespe GE, et al. . Th2 cytokines inhibit lymphangiogenesis. PLoS ONE (2015) 10:e0126908. 10.1371/journal.pone.0126908
    1. Kataru RP, Kim H, Jang C, Choi DK, Koh BI, Kim M, et al. . T lymphocytes negatively regulate lymph node lymphatic vessel formation. Immunity (2011) 34:96–107. 10.1016/j.immuni.2010.12.016
    1. Rehal S, Blanckaert P, Roizes S, von der Weid PY. (2009). Characterization of biosynthesis and modes of action of prostaglandin E2 and prostacyclin in guinea pig mesenteric lymphatic vessels. Br. J. Pharmacol. 158, 1961–1970. 10.1111/j.1476-5381.2009.00493.x
    1. Aldrich MB, Sevick-Muraca EM. Cytokines are systemic effectors of lymphatic function in acute inflammation. Cytokine (2013) 64:362–9. 10.1016/j.cyto.2013.05.015
    1. Cromer WE, Zawieja SD, Tharakan B, Childs EW, Newell MK, Zawieja DC. The effects of inflammatory cytokines on lymphatic endothelial barrier function. Angiogenesis (2014) 17:395–406. 10.1007/s10456-013-9393-2
    1. Nagy JA, Vasile E, Feng D, Sundberg C, Brown LF, Detmar MJ, et al. . Vascular permeability factor/vascular endothelial growth factor induces lymphangiogenesis as well as angiogenesis. J Exp Med. (2002) 196:1497–506. 10.1084/jem.20021244
    1. Zhang Y, Lu Y, Ma L, Cao X, Xiao J, Chen J, et al. . Activation of vascular endothelial growth factor receptor-3 in macrophages restrains TLR4-NF-κB signaling and protects against endotoxin shock. Immunity (2014) 40:501–14. 10.1016/j.immuni.2014.01.013
    1. Polzer K, Baeten D, Soleiman A, Distler J, Gerlag DM, Tak PP, et al. . Tumour necrosis factor blockade increases lymphangiogenesis in murine and human arthritic joints. Ann Rheum Dis. (2008) 67:1610–6. 10.1136/ard.2007.083394
    1. Hos D, Saban DR, Bock F, Regenfuss B, Onderka J, Masli S, et al. . Suppression of inflammatory corneal lymphangiogenesis by application of topical corticosteroids. Arch Ophthalmol. (2011) 129:445–52. 10.1001/archophthalmol.2011.42
    1. Yao L-C, Baluk P, Feng J, McDonald DM. Steroid-resistant lymphatic remodeling in chronically inflamed mouse airways. Am J Pathol. (2010) 176:1525–41. 10.2353/ajpath.2010.090909
    1. Iwata C, Kano MR, Komuro A, Oka M, Kiyono K, Johansson E, et al. . Inhibition of cyclooxygenase-2 suppresses lymph node metastasis via reduction of lymphangiogenesis. Cancer Res. (2007) 67:10181–9. 10.1158/0008-5472.CAN-07-2366
    1. Jamieson T, Cook DN, Nibbs RJB, Rot A, Nixon C, McLean P, et al. . The chemokine receptor D6 limits the inflammatory response in vivo. Nat Immunol. (2005) 6:403–11. 10.1038/ni1182
    1. Vetrano S, Borroni EM, Sarukhan A, Savino B, Bonecchi R, Correale C, et al. . The lymphatic system controls intestinal inflammation and inflammation-associated Colon Cancer through the chemokine decoy receptor D6. Gut (2010) 59:197–206. 10.1136/gut.2009.183772
    1. Karaman S, Hollmén M, Yoon SY, Alkan HF, Alitalo K, Wolfrum C, et al. . Transgenic overexpression of VEGF-C induces weight gain and insulin resistance in mice. Sci Rep. (2016) 6:31566. 10.1038/srep31566
    1. Karaman S, Hollmén M, Robciuc MR, Alitalo A, Nurmi H, Morf B, et al. . Blockade of VEGF-C and VEGF-D modulates adipose tissue inflammation and improves metabolic parameters under high-fat diet. Mol Metab. (2015) 4:93–105. 10.1016/j.molmet.2014.11.006
    1. Skobe M, Hamberg LM, Hawighorst T, Schirner M, Wolf GL, Alitalo K, et al. . Concurrent induction of lymphangiogenesis, angiogenesis, and macrophage recruitment by vascular endothelial growth factor-C in melanoma. Am J Pathol. (2001) 159:893–903. 10.1016/S0002-9440(10)61765-8
    1. Hirakawa S, Brown LF, Kodama S, Paavonen K, Alitalo K, Detmar M. VEGF-C-induced lymphangiogenesis in sentinel lymph nodes promotes tumor metastasis to distant sites. Blood (2007) 109:1010–7. 10.1182/blood-2006-05-021758
    1. Schwager S, Renner S, Hemmerle T, Karaman S, Proulx ST, Fetz R, et al. . Antibody-mediated delivery of VEGF-C potently reduces chronic skin inflammation. JCI Insight (2018) 3:1983. 10.1172/jci.insight.124850

Source: PubMed

스폰서 및 공동 작업자

건강 상태

약물 개입

3
구독하다