The role of endothelial cell-selective adhesion molecule (ESAM) in neutrophil emigration into inflamed tissues

  • Stefan Butz
  • Dietmar Vestweber
Part of the Progress in Inflammation Research book series (PIR)


Leukocyte emigration into inflamed tissues is among the most intensely pursued topics in the field of inflammation. Research focuses on the molecular factors activating endothelial cells and leukocytes, the adhesive molecules facilitating the contact between both cell types and the mechanisms allowing leukocytes to transmigrate through the blood vessel endothelium. In the last few years, studies have been intensified to understand how leukocytes, once captured to the vessel wall overcome the barrier made of endothelial cells linked to each other by interendothelial junctions. The mechanisms by which these leukocytes traverse the endothelial cell layer to reach the underlying tissue, a process called diapedesis, are largely unknown. Whereas convincing evidence has been published that polymorphonuclear leukocytes (PMN) can indeed migrate through endothelial cells in a transcellular fashion in vivo [1] as well as in vitro [2], careful quantitative analysis has demonstrated that at least in vitro the majority of PMNs and other leukocytes migrate via a paracellular route through the contact areas between endothelial cells [2, 3]. Consequently, a number of endothelial cell contact proteins such as PECAM-1, members of the junctional adhesion molecule family (JAM-A, -B and -C), CD99 and ICAM-2 have been reported to support leukocyte extravasation [4, 5, 6, 7] . PECAM-1 was the first of these proteins that was identified in the context of leukocyte extravasation [8]. Its relevance for neutrophil extravasation is well established [9]. Although PECAM-1, JAM-A and ICAM-2 were shown by intravital microscopy to be involved in the transmigration process in vivo, the detailed molecular mechanism by which they participate in the process is still unknown.


Transendothelial Migration Junctional Adhesion Molecule Leukocyte Extravasation Endothelial Tight Junction Neutrophil Extravasation 


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  1. 1.
    Feng D, Nagy JA, Pyne K, Dvorak HF, Dvorak AM (1998) Neutrophils emigrate from venules by a transendothelial cell pathway in response to FMLP. J Exp Med 187: 903–915PubMedCrossRefGoogle Scholar
  2. 2.
    Carman CV, Springer TA (2004) A transmigratory cup in leukocyte diapedesis both through individual vascular endothelial cells and between them. J Cell Biol 167: 377–388PubMedCrossRefGoogle Scholar
  3. 3.
    Millan JL, Hewlett L, Glyn M, Toomre D, Clark P, Ridley AJ (2006) Lymphocyte transcellular migration occurs through recruitment of endothelial ICAM-1 to caveola-and F-actin-rich domains. Nat Cell Biol 8: 113–123PubMedCrossRefGoogle Scholar
  4. 4.
    Muller WA (2003) Leukocyte-endothelial-cell interactions in leukocyte transmigration and the inflammatory response. Trends Immunol 24: 326–333CrossRefGoogle Scholar
  5. 5.
    Imhof BA, Aurrand-Lions M (2004) Adhesion mechanisms regulating the migration of monocytes. Nat Rev Immunol 4: 432–444PubMedCrossRefGoogle Scholar
  6. 6.
    Bixel G, Kloep S, Butz S, Petri B, Engelhardt B, Vestweber D (2004) Mouse CD99 participates in T cell recruitment into inflamed skin. Blood 104: 3205–3213PubMedCrossRefGoogle Scholar
  7. 7.
    Huang MT, Larbi KY, Scheiermann C, Woodfin A, Gerwin N, Haskard DO, Nourshargh S (2006) ICAM-2 mediates neutrophil transmigration in vivo: Evidence for stimulus specificity and a role in PECAM-1-independent transmigration. Blood 107: 4721–4727PubMedCrossRefGoogle Scholar
  8. 8.
    Muller WA, Weigl SA, Deng X, Phillips DM (1993) PECAM-1 is required for transendothelial migration of leukocytes. J Exp Med 178: 449–460PubMedCrossRefGoogle Scholar
  9. 9.
    Schenkel AR, Chew TW, Muller WA (2004) Platelet endothelial cell adhesion molecule deficiency or blockade significantly reduces leukocyte emigration in a majority of mouse strains. J Immunol 173: 6403–6408PubMedGoogle Scholar
  10. 10.
    Gotsch U, Borges E, Bosse R, Böggemeyer E, Simon M, Mossmann H, Vestweber D (1997) VE-cadherin antibody accelerates neutrophil recruitment in vivo. J Cell Sci 110: 583–588PubMedGoogle Scholar
  11. 11.
    Hirata K, Ishida T, Penta K, Rezaee M, Yang E, Wohlgemuth J, Quertermous T (2001) Cloning of an immunoglobulin family adhesion molecule selectively expressed by endothelial cells. J Biol Chem 276: 16223–16231CrossRefGoogle Scholar
  12. 12.
    Nasdala I, Wolburg-Buchholz K, Wolburg H, Kuhn A, Ebnet K, Brachtendorf G, Samulowitz U, Kuster B, Engelhardt B, Vestweber D et al (2002) A transmembrane tight junction protein selectively expressed on endothelial cells and platelets. J Biol Chem 277: 16294–16303PubMedCrossRefGoogle Scholar
  13. 13.
    Chretien I, Robert J, Marcuz A, Garcia-Sanz JA, Courtet M, Du Pasquier L (1996) CTX, a novel molecule specifically expressed on the surface of cortical thymocytes in Xenopus. Eur J Immunol 26: 780–791PubMedCrossRefGoogle Scholar
  14. 14.
    Chretien I, Marcuz A, Courtet M, Katevuo K, Vainio O, Heath JK, White SJ, Du Pasquier L (1998) CTX, a Xenopus thymocyte receptor, defines a molecular family conserved throughout vertebrates. Eur J Immunol 28: 4094–4104PubMedCrossRefGoogle Scholar
  15. 15.
    Tomko RP, Xu R, Philipson L (1997) HCAR and MCAR: the human and mouse cellular receptors for subgroup C adenoviruses and group B coxsackieviruses. Proc Natl Acad Sci USA 94: 3352–3356PubMedCrossRefGoogle Scholar
  16. 16.
    Bergelson JM, Cunningham JA, Droguett G, Kurt-Jones EA, Krithivas A, Hong JS, Horwitz MS, Crowell RL, Finberg RW (1997) Isolation of a common receptor for Coxsackie B viruses and adenoviruses 2 and 5. Science 275: 1320–1323PubMedCrossRefGoogle Scholar
  17. 17.
    Suzu S, Hayashi Y, Harumi T, Nomaguchi K, Yamada M, Hayasawa H, Motoyoshi K (2002) Molecular cloning of a novel immunoglobulin superfamily gene preferentially expressed by brain and testis. Biochem Biophys Res Commun 296: 1215–1221PubMedCrossRefGoogle Scholar
  18. 18.
    Hirabayashi S, Tajima M, Yao I, Nishimura W, Mori H, Hata Y (2003) JAM4, a junctional cell adhesion molecule interacting with a tight junction protein, MAGI-1. Mol Cell Biol23:4267–4282PubMedCrossRefGoogle Scholar
  19. 19.
    Martin-Padura I, Lostaglio S, Schneemann M, Williams L, Romano M, Fruscella P, Panzeri C, Stoppacciaro A, Ruco L, Villa A et al (1998) Junctional adhesion molecule, a novel member of the immunoglobulin superfamily that distributes at intercellular junctions and modulates monocyte transmigration. J Cell Biol 142: 117–127PubMedCrossRefGoogle Scholar
  20. 20.
    Malergue F, Galland F, Martin F, Mansuelle P, Aurrand-Lions M, Naquet P (1998) A novel immunoglobulin superfamily junctional molecule expressed by antigen presenting cells, endothelial cells and platelets. Mol Immunol 35: 1111–1119PubMedCrossRefGoogle Scholar
  21. 21.
    Aurrand-Lions MA, Duncan L, Du Pasquier L, Imhof BA(2000) Cloning of JAM-2 and JAM-3: an emerging junctional adhesion molecular family? Curr Top Microbiol Immunol 251: 91–98PubMedGoogle Scholar
  22. 22.
    Cunningham SA, Arrate MP, Rodriguez JM, Bjercke RJ, Vanderslice P, Morris AP, Brock TA (2000) A novel protein with homology to the junctional adhesion molecule. Characterization of leukocyte interactions. J Biol Chem 275: 34750–34756PubMedCrossRefGoogle Scholar
  23. 23.
    Palmeri D, van Zante A, Huang CC, Hemmerich S, Rosen SD (2000) Vascular endothelial junction-associated molecule, a novel member of the immunoglobulin superfamily, is localized to intercellular boundaries of endothelial cells. J Biol Chem 275: 19139–19145PubMedCrossRefGoogle Scholar
  24. 24.
    Wegmann F, Ebnet K, Du Pasquier L, Vestweber D, Butz S(2004) Endothelial adhesion molecule ESAM binds directly to the multidomain adaptor MAGI-1 and recruits it to cell contacts. Exp Cell Res 300: 121–133PubMedCrossRefGoogle Scholar
  25. 25.
    Arrate MP, Rodriguez JM, Tran TM, Brock TA, Cunningham SA (2001) Cloning of human junctional adhesion molecule 3 (JAM3) and its identification as the JAM2 counter-receptor. J Biol Chem 276: 45826–45832PubMedCrossRefGoogle Scholar
  26. 26.
    Itoh M, Sasaki H, Furuse M, Ozaki H, Kita T, Tsukita S (2001) Junctional adhesion molecule (JAM) binds to PAR-3: a possible mechanism for the recruitment of PAR-3 to tight junctions. J Cell Biol 154: 491–497PubMedCrossRefGoogle Scholar
  27. 27.
    Ebnet K, Suzuki A, Horikoshi Y, Hirose T, Meyer-zu-Brickwedde MK, Ohno S, Vestweber D (2001) The cell polarity protein ASIP/PAR-3 directly associates with junctional adhesion molecule (JAM). EMBO J 20:3738–3748PubMedCrossRefGoogle Scholar
  28. 28.
    Ebnet K, Aurrand-Lions M, Kuhn A, Kiefer F, Butz S, Zander K, Meyer zu Brickwedde MK, Suzuki A, Imhof BA, Vestweber D (2003) The junctional adhesion molecule (JAM) family members JAM-2 and JAM-3 associate with the cell polarity protein PAR-3: a possible role for JAMs in endothelial cell polarity. J Cell Sci 116: 3879–3891PubMedCrossRefGoogle Scholar
  29. 29.
    Ebnet K, Suzuki A, Ohno S, Vestweber D (2004) Junctional adhesion molecules (JAMs): more molecules with dual functions? J Cell Sci 117: 19–29PubMedCrossRefGoogle Scholar
  30. 30.
    Liang TW, Chiu HH, Gurney A, Sidle A, Tumas DB, Schow P, Foster J, Klassen T, Dennis K, De Marco RA et al (2002) Vascular endothelial-junctional adhesion molecule (VE-JAM)/JAM 2 interacts with T, NK, and dendritic cells through JAM 3. J Immunol 168:1618–1626PubMedGoogle Scholar
  31. 31.
    Wegmann F, Petri J, Khandoga AG, Moser C, Khandoga A, Volkery S, Li H, Nasdala I, Brandau O, Fassler R et al (2006) ESAM supports neutrophil extravasation, activation of Rho and VEGF-induced vascular permeability. J Exp Med 203: 1671–1677PubMedCrossRefGoogle Scholar
  32. 32.
    Ishida T, Kundu RK, Yang E, Hirata K, Ho YD, Quertermous T (2003) Targeted disruption of endothelial cell-selective adhesion molecule inhibits angiogenic processes in vitro and in vivo. J Biol Chem 278: 34598–34604PubMedCrossRefGoogle Scholar
  33. 33.
    Ostermann G, Weber KS, Zernecke A, Schroder A, Weber C (2002) JAM-1 is a ligand of the beta(2) integrin LFA-1 involved in transendothelial migration of leukocytes. Nat Immunol 3: 151–158PubMedCrossRefGoogle Scholar
  34. 34.
    Mempel TR, Moser C, Hutter J, Kuebler WM, Krombach F (2003) Visualization of leukocyte transendothelial and interstitial migration using reflected light oblique transillumination in intravital video microscopy. J Vasc Res 40: 435–441PubMedCrossRefGoogle Scholar
  35. 35.
    Wakelin MW, Sanz MJ, Dewar A, Albelda SM, Larkin SW, Boughton-Smith N, Williams TJ, Nourshargh S (1996) An anti-platelet-endothelial cell adhesion molecule-1 antibody inhibits leukocyte extravasation from mesenteric microvessels in vivo by blocking the passage through the basement membrane. J Exp Med 184: 229–239PubMedCrossRefGoogle Scholar
  36. 36.
    Khandoga A, Kessler JS, Meissner H, Hanschen M, Corada M, Motoike T, Enders G, Dejana E, Krombach F (2005) Junctional adhesion molecule-A deficiency increases hepatic ischemia-reperfusion injury despite reduction of neutrophil transendothelial migration. Blood 106: 725–733PubMedCrossRefGoogle Scholar
  37. 37.
    Orlova VV, Economopoulou M, Lupu F, Santoso S, Chavakis T (2006) Junctional adhesion molecule-C regulates vascular endothelial permeability by modulating VE-cadherin-mediated cell-cell contacts. J Exp Med 203: 2703–2714PubMedCrossRefGoogle Scholar
  38. 38.
    Strey A, Janning A, Barth H, Gerke V (2002) Endothelial Rho signaling is required for monocyte transendothelial migration. FEBS Lett 517: 261–266PubMedCrossRefGoogle Scholar
  39. 39.
    Saito H, Minamiya Y, Saito S, Ogawa J (2002) Endothelial Rho and Rho kinase regulate neutrophil migration via endothelial myosin light chain phosphorylation. J Leukoc Biol 72: 829–836PubMedGoogle Scholar
  40. 40.
    Stamatovic SM, Keep RF, Kunkel SL, Andjelkovic AV (2003) Potential role of MCP-1 in endothelial cell tight junction ‘opening’: signaling via Rho and Rho kinase. J Cell Sci 116:4615–4628PubMedCrossRefGoogle Scholar
  41. 41.
    Stamatovic SM, Dimitrijevic OB, Keep RF, Andjelkovic AV (2006) Protein kinase Calpha: RhoA cross talk in CCL2-induced alterations in brain endothelial permeability. J Biol Chem 281: 8379–8388PubMedCrossRefGoogle Scholar
  42. 42.
    Persidsky Y, Heilman D, Haorah J, Zelivyanskaya M, Persidsky R, Weber GA, Shimokawa H, Kaibuchi K, Ikezu T (2006) Rho-mediated regulation of tight junctions during monocyte migration across blood-brain barrier in HIV-1 encephalitis (HIVE). Blood 107:4770–4780PubMedCrossRefGoogle Scholar
  43. 43.
    Dobrosotskaya IY (2001) Identification of mNET1 as a candidate ligand for the first PDZ domain of MAGI-1. Biochem Biophys Res Commun 283: 969–975PubMedCrossRefGoogle Scholar
  44. 44.
    Etienne S, Adamson P, Greenwood J, Strosberg AD, Cazaubon S, Couraud PO (1998) ICAM-1 signaling pathways associated with Rho activation in microvascular brain endothelial cells. J Immunol 161: 5755–5761PubMedGoogle Scholar
  45. 45.
    Adamson P, Etienne S, Couraud PO, Calder V, Greenwood J (1999) Lymphocyte migration through brain endothelial cell monolayers involves signaling through endothelial ICAM-1 via a rho-dependent pathway. J Immunol 162: 2964–2973PubMedGoogle Scholar
  46. 46.
    Esser S, Lampugnam MG, Corada M, Dejana E, Risau W (1998) Vascular endothelial growth factor induces VE-cadherin tyrosine phosphorylation in endothelial cells. J Cell Sci 111:1853–1865PubMedGoogle Scholar
  47. 47.
    Antonetti DA, Barber AJ, Hollinger LA, Wolpert EB, Gardner TW (1999) Vascular endothelial growth factor induces rapid phosphorylation of tight junction proteins occludin and zonula occluden 1. A potential mechanism for vascular permeability in diabetic retinopathy and tumors. J Biol Chem274: 23463–23467PubMedCrossRefGoogle Scholar
  48. 48.
    Pedram A, Razandi M, Levin ER (2002) Deciphering vascular endothelial cell growth factor/vascular permeability factor signaling to vascular permeability. Inhibition by atrial natriuretic peptide. J Biol Chem 277: 44385–44398PubMedCrossRefGoogle Scholar
  49. 49.
    Weis S, Shintani S, Weber A, Kirchmair R, Wood M, Cravens A, McSharry H, Iwakura A, Yoon YS, Himes N et al (2004) Src blockade stabilizes a Flk/cadherin complex, reducing edema and tissue injury following myocardial infarction. J Clin Invest 113: 885–894PubMedCrossRefGoogle Scholar
  50. 50.
    Gavard J, Gutkind JS (2006) VEGF controls endothelial-cell permeability by promoting the β-arrestin-dependent endocytosis of VE-cadherin. Nat Cell Biol 8: 1223–1234PubMedCrossRefGoogle Scholar
  51. 51.
    Eliceiri BP, Paul R, Schwartzberg PL, Hood JD, Leng J, Cheresh DA (1999) Selective requirement for Src kinases during VEGF-induced angiogenesis and vascular permeability. Mol Cell 4: 915–924PubMedCrossRefGoogle Scholar

Copyright information

© Birkhäuser Verlag Basel/Switzerland 2007

Authors and Affiliations

  • Stefan Butz
    • 1
  • Dietmar Vestweber
    • 1
  1. 1.Max-Planck-Institute for Molecular BiomedicineMünsterGermany

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