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DOI: 10.1160/TH08-12-0844
Novel aspects in the regulation of the leukocyte adhesion cascade
Publication History
Received:
31 December 2008
Accepted after minor revision:
10 February 2009
Publication Date:
22 November 2017 (online)
![](https://www.thieme-connect.de/media/10.1055-s-00035024/200902/lookinside/thumbnails/10-1160-th08-12-0844-1.jpg)
Summary
Leukocyte recruitment plays a major role in the immune response to infectious pathogens and during inflammatory and autoimmune disorders. The process of leukocyte extravasation from the blood into the inflamed tissue requires a complex cascade of adhesive events between the leukocytes and the endothelium including leukocyte rolling, adhesion and transendothelial migration. Leukocyte-endothelial interactions are mediated by tightly regulated binding interactions between adhesion receptors on both cells. In this regard, leukocyte adhesion onto the endothelium is governed by leukocyte integrins and their endothelial counter-receptors of the immunoglobulin superfamily. The present review will focus on novel aspects with respect to the modulation of the leukocyte adhesion cascade.
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References
- 1 Luster AD, Alon R, von Andrian UH. Immune cell migration in inflammation: present and future therapeutic targets. Nat Immunol 2005; 06: 1182-1190.
- 2 Springer TA. Traffic signals for lymphocyte recirculation and leukocyte emigration: the multistep paradigm. Cell 1994; 76: 301-314.
- 3 Ley K, Laudanna C, Cybulsky MI. et al. Getting to the site of inflammation: the leukocyte adhesion cascade updated. Nat Rev Immunol 2007; 07: 678-689.
- 4 Rao RM, Yang L, Garcia-Cardena G. et al. Endothelial-dependent mechanisms of leukocyte recruitment to the vascular wall. Circ Res 2007; 101: 234-247.
- 5 Keiper T, Santoso S, Nawroth PP. et al. The role of junctional adhesion molecules in cell-cell interactions. Histol Histopathol 2005; 20: 197-203.
- 6 Carlos TM, Harlan JM. Leukocyte-endothelial adhesion molecules. Blood 1994; 84: 2068-2101.
- 7 Muller WA. Leukocyte-endothelial cell interactions in the inflammatory response. Lab Invest 2002; 82: 521-533.
- 8 Schenkel AR, Mamdouh Z, Muller WA. Locomotion of monocytes on endothelium is a critical step during extravasation. Nat Immunol 2004; 05: 393-400.
- 9 Imhof BA, Aurrand-Lions M. Adhesion mechanisms regulating the migration of monocytes. Nat Rev Immunol 2004; 04: 432-444.
- 10 Kinashi T. Intracellular signalling controlling integrin activation in lymphocytes. Nat Rev Immunol 2005; 05: 546-559.
- 11 Vestweber D. Adhesion and signaling molecules controlling the transmigration of leukocytes through endothelium. Immunol Rev 2007; 218: 178-196.
- 12 McEver RP. Selectins: lectins that initiate cell adhesion under flow. Curr Opin Cell Biol 2002; 14: 581-586.
- 13 McEver RP, Cummings RD. Role of PSGL-1 binding to selectins in leukocyte recruitment. J Clin Invest 1997; 100: S97-103.
- 14 Smith ML, Olson TS, Ley K. CXCR2- and E-selectin-induced neutrophil arrest during inflammation in vivo. J Exp Med 2004; 200: 935-939.
- 15 Salas A, Shimaoka M, Kogan AN. et al. Rolling adhesion through an extended conformation of integrin alphaLbeta2 and relation to alpha I and beta I-like domain interaction. Immunity 2004; 20: 393-406.
- 16 Zarbock A, Lowell CA, Ley K. Spleen tyrosine kinase Syk is necessary for E-selectin-induced alpha(L)beta(2) integrin-mediated rolling on intercellular adhesion molecule-1. Immunity 2007; 26: 773-783.
- 17 Rot A, von Andrian UH. Chemokines in innate and adaptive host defense: basic chemokinese grammar for immune cells. Annu Rev Immunol 2004; 22: 891-928.
- 18 Yonekawa K, Harlan JM. Targeting leukocyte integrins in human diseases. J Leukoc Biol 2005; 77: 129-140.
- 19 Chavakis T, Bierhaus A, Al-Fakhri N. et al. The pattern recognition receptor (RAGE) is a counterreceptor for leukocyte integrins: a novel pathway for inflammatory cell recruitment. J Exp Med 2003; 198: 1507-1515.
- 20 Gahmberg CG, Valmu L, Fagerholm S. et al. Leukocyte integrins and inflammation. Cell Mol Life Sci 1998; 54: 549-555.
- 21 Staunton DE, Dustin ML, Springer TA. Functional cloning of ICAM-2, a cell adhesion ligand for LFA-1 homologous to ICAM-1. Nature 1989; 339: 61-64.
- 22 Fawcett J, Holness CL, Needham LA. et al. Molecular cloning of ICAM-3, a third ligand for LFA-1, constitutively expressed on resting leukocytes. Nature 1992; 360: 481-484.
- 23 Bailly P, Tontti E, Hermand P. et al. The red cell LW blood group protein is an intercellular adhesion molecule which binds to CD11/CD18 leukocyte integrins. Eur J Immunol 1995; 25: 3316-3320.
- 24 Gahmberg CG, Tian L, Ning L. et al. ICAM-5--a novel two-facetted adhesion molecule in the mammalian brain. Immunol Lett 2008; 117: 131-135.
- 25 Phillipson M, Heit B, Colarusso P. et al. Intraluminal crawling of neutrophils to emigration sites: a molecularly distinct process from adhesion in the recruitment cascade. J Exp Med 2006; 203: 2569-2575.
- 26 Nourshargh S, Marelli-Berg FM. Transmigration through venular walls: a key regulator of leukocyte phenotype and function. Trends Immunol 2005; 26: 157-165.
- 27 Shaw SK, Ma S, Kim MB. et al. Coordinated redistribution of leukocyte LFA-1 and endothelial cell ICAM-1 accompany neutrophil transmigration. J Exp Med 2004; 200: 1571-1580.
- 28 Carman CV, Springer TA. A transmigratory cup in leukocyte diapedesis both through individual vascular endothelial cells and between them. J Cell Biol 2004; 167: 377-388.
- 29 Yang L, Froio RM, Sciuto TE. et al. ICAM-1 regulates neutrophil adhesion and transcellular migration of TNF-alpha-activated vascular endothelium under flow. Blood 2005; 106: 584-592.
- 30 Huang MT, Larbi KY, Scheiermann C. et al. ICAM-2 mediates neutrophil transmigration in vivo: evidence for stimulus specificity and a role in PECAM-1-independent transmigration. Blood 2006; 107: 4721-4727.
- 31 Bazzoni G, Dejana E. Endothelial cell-to-cell junctions: molecular organization and role in vascular homeostasis. Physiol Rev 2004; 84: 869-901.
- 32 Shaw SK, Bamba PS, Perkins BN. et al. Real-time imaging of vascular endothelial-cadherin during leukocyte transmigration across endothelium. J Immunol 2001; 167: 2323-2330.
- 33 Gotsch U, Borges E, Bosse R. et al. VE-cadherin antibody accelerates neutrophil recruitment in vivo. J Cell Sci 1997; 110: 583-588.
- 34 Orlova VV, Chavakis T. Regulation of vascular endothelial permeability by junctional adhesion molecules (JAM). Thromb Haemost 2007; 98: 327-332.
- 35 Bradfield PF, Nourshargh S, Aurrand-Lions M. et al. JAM family and related proteins in leukocyte migration (Vestweber series). Arterioscler Thromb Vasc Biol 2007; 27: 2104-2112.
- 36 Weber C, Fraemohs L, Dejana E. The role of junctional adhesion molecules in vascular inflammation. Nat Rev Immunol 2007; 07: 467-477.
- 37 Santoso S, Orlova VV, Song K. et al. The homophilic binding of junctional adhesion molecule-C mediates tumor cell-endothelial cell interactions. J Biol Chem 2005; 280: 36326-36333.
- 38 Kostrewa D, Brockhaus M, D’Arcy A. et al. X-ray structure of junctional adhesion molecule: structural basis for homophilic adhesion via a novel dimerization motif. Embo J 2001; 20: 4391-4398.
- 39 Santoso S, Sachs UJ, Kroll H. et al. The junctional adhesion molecule 3 (JAM-3) on human platelets is a counterreceptor for the leukocyte integrin Mac-1. J Exp Med 2002; 196: 679-691.
- 40 Ostermann G, Weber KS, Zernecke A. et al. JAM-1 is a ligand of the beta(2) integrin LFA-1 involved in transendothelial migration of leukocytes. Nat Immunol 2002; 03: 151-158.
- 41 Cunningham SA, Rodriguez JM, Arrate MP. et al. JAM2 interacts with alpha4beta1. Facilitation by JAM3. J Biol Chem 2002; 277: 27589-27592.
- 42 Arrate MP, Rodriguez JM, Tran TM. et al. Cloning of human junctional adhesion molecule 3 (JAM3) and its identification as the JAM2 counter-receptor. J Biol Chem 2001; 276: 45826-45832.
- 43 Lamagna C, Meda P, Mandicourt G. et al. Dual interaction of JAM-C with JAM-B and alpha(M)beta2 integrin: function in junctional complexes and leukocyte adhesion. Mol Biol Cell 2005; 16: 4992-5003.
- 44 Del Maschio A, De Luigi A, Martin-Padura I. Leukocyte recruitment in the cerebrospinal fluid of mice with experimental meningitis is inhibited by an antibody to junctional adhesion molecule (JAM). J Exp Med 1999; 190: 1351-1356.
- 45 Corada M, Chimenti S, Cera MR. et al. Junctional adhesion molecule-A-deficient polymorphonuclear cells show reduced diapedesis in peritonitis and heart ischemia-reperfusion injury. Proc Natl Acad Sci USA 2005; 102: 10634-10639.
- 46 Khandoga A, Kessler JS, Meissner H. et al. Junctional adhesion molecule-A deficiency increases hepatic ischemia-reperfusion injury despite reduction of neutrophil transendothelial migration. Blood 2005; 106: 725-733.
- 47 Chavakis T, Keiper T, Matz-Westphal R. et al. The junctional adhesion molecule-C promotes neutrophil transendothelial migration in vitro and in vivo. J Biol Chem 2004; 279: 55602-55608.
- 48 Aurrand-Lions M, Lamagna C, Dangerfield JP. et al. Junctional adhesion molecule-C regulates the early influx of leukocytes into tissues during inflammation. J Immunol 2005; 174: 6406-6415.
- 49 Orlova VV, Economopoulou M, Lupu F. et al. Junctional adhesion molecule-C regulates vascular endothelial permeability by modulating VE-cadherinmediated cell-cell contacts. J Exp Med 2006; 203: 2703-2714.
- 50 Wegmann F, Petri B, Khandoga AG. et al. ESAM supports neutrophil extravasation, activation of Rho, and VEGF-induced vascular permeability. J Exp Med 2006; 203: 1671-1677.
- 51 Muller WA. Leukocyte-endothelial-cell interactions in leukocyte transmigration and the inflammatory response. Trends Immunol 2003; 24: 327-334.
- 52 Newman PJ. The biology of PECAM-1. J Clin Invest 1997; 100: S25-29.
- 53 Muller WA, Weigl SA, Deng X. et al. PECAM-1 is required for transendothelial migration of leukocytes. J Exp Med 1993; 178: 449-460.
- 54 Bogen S, Pak J, Garifallou M. et al. Monoclonal antibody to murine PECAM-1 (CD31) blocks acute inflammation in vivo. J Exp Med 1994; 179: 1059-1064.
- 55 Liao F, Ali J, Greene T. et al. Soluble domain 1 of platelet-endothelial cell adhesion molecule (PECAM) is sufficient to block transendothelial migration in vitro and in vivo. J Exp Med 1997; 185: 1349-1357.
- 56 Mamdouh Z, Chen X, Pierini LM. et al. Targeted recycling of PECAM from endothelial surface-connected compartments during diapedesis. Nature 2003; 421: 748-753.
- 57 Hua CT, Gamble JR, Vadas MA. et al. Recruitment and activation of SHP-1 protein-tyrosine phosphatase by human platelet endothelial cell adhesion molecule-1 (PECAM-1). Identification of immunoreceptor tyrosine-based inhibitory motif-like binding motifs and substrates. J Biol Chem 1998; 273: 28332-28340.
- 58 Pumphrey NJ, Taylor V, Freeman S. et al. Differential association of cytoplasmic signalling molecules SHP-1, SHP-2, SHIP and phospholipase C-gamma1 with PECAM-1/CD31. FEBS Lett 1999; 450: 77-83.
- 59 Dangerfield J, Larbi KY, Huang MT. et al. PECAM-1 (CD31) homophilic interaction up-regulates alpha6beta1 on transmigrated neutrophils in vivo and plays a functional role in the ability of alpha6 integrins to mediate leukocyte migration through the perivascular basement membrane. J Exp Med 2002; 196: 1201-1211.
- 60 Springer TA, Thompson WS, Miller LJ. et al. Inherited deficiency of the Mac-1, LFA-1, p150,95 glycoprotein family and its molecular basis. J Exp Med 1984; 160: 1901-1918.
- 61 Ding ZM, Babensee JE, Simon SI. et al. Relative contribution of LFA-1 and Mac-1 to neutrophil adhesion and migration. J Immunol 1999; 163: 5029-5038.
- 62 Mizgerd JP, Kubo H, Kutkoski GJ. et al. Neutrophil emigration in the skin, lungs, and peritoneum: different requirements for CD11/CD18 revealed by CD18-deficient mice. J Exp Med 1997; 186: 1357-1364.
- 63 Berlin-Rufenach C, Otto F, Mathies M. et al. Lymphocyte migration in lymphocyte function-associated antigen (LFA)-1-deficient mice. J Exp Med 1999; 189: 1467-1478.
- 64 Steinman L. Blocking adhesion molecules as therapy for multiple sclerosis: natalizumab. Nat Rev Drug Discov 2005; 04: 510-518.
- 65 Lebwohl M, Tyring SK, Hamilton TK. et al. A novel targeted T-cell modulator, efalizumab, for plaque psoriasis. N Engl J Med 2003; 349: 2004-2013.
- 66 Laudanna C, Alon R. Right on the spot. Chemokine triggering of integrin-mediated arrest of rolling leukocytes. Thromb Haemost 2006; 95: 5-11.
- 67 Salas A, Shimaoka M, Chen S. et al. Transition from rolling to firm adhesion is regulated by the conformation of the I domain of the integrin lymphocyte function-associated antigen-1. J Biol Chem 2002; 277: 50255-50262.
- 68 Salas A, Shimaoka M, Phan U. et al. Transition from rolling to firm adhesion can be mimicked by extension of integrin alphaLbeta2 in an intermediate affinity state. J Biol Chem 2006; 281: 10876-10882.
- 69 Carman CV, Springer TA. Integrin avidity regulation: are changes in affinity and conformation underemphasized?. Curr Opin Cell Biol 2003; 15: 547-556.
- 70 Dustin ML, Bivona TG, Philips MR. Membranes as messengers in T cell adhesion signaling. Nat Immunol 2004; 05: 363-372.
- 71 Shimaoka M, Xiao T, Liu JH. et al. Structures of the alpha L I domain and its complex with ICAM-1 reveal a shape-shifting pathway for integrin regulation. Cell 2003; 112: 99-111.
- 72 Takagi J, Petre BM, Walz T. et al. Global conformational rearrangements in integrin extracellular domains in outside-in and inside-out signaling. Cell 2002; 110: 599-511.
- 73 Takagi J, Springer TA. Integrin activation and structural rearrangement. Immunol Rev 2002; 186: 141-163.
- 74 Luo BH, Carman CV, Springer TA. Structural basis of integrin regulation and signaling. Annu Rev Immunol 2007; 25: 619-647.
- 75 Kinashi T. Integrin regulation of lymphocyte trafficking: lessons from structural and signaling studies. Adv Immunol 2007; 93: 185-227.
- 76 Nishida N, Xie C, Shimaoka M. et al. Activation of leukocyte beta2 integrins by conversion from bent to extended conformations. Immunity 2006; 25: 583-594.
- 77 Kinashi T. Adhere upright: a switchblade-like extension of beta2 integrins. Immunity 2006; 25: 521-522.
- 78 Kim M, Carman CV, Springer TA. Bidirectional transmembrane signaling by cytoplasmic domain separation in integrins. Science 2003; 301: 1720-1725.
- 79 Bazzoni G, Hemler ME. Are changes in integrin affinity and conformation overemphasized?. Trends Biochem Sci 1998; 23: 30-34.
- 80 Chan JR, Cybulsky MI. Detection of high-affinity alpha4-integrin upon leukocyte stimulation by chemoattractants or chemokines. Methods Mol Biol 2004; 239: 261-268.
- 81 Giagulli C, Scarpini E, Ottoboni L. et al. RhoA and zeta PKC control distinct modalities of LFA-1 activation by chemokines: critical role of LFA-1 affinity triggering in lymphocyte in vivo homing. Immunity 2004; 20: 25-35.
- 82 Grabovsky V, Feigelson S, Chen C. et al. Subsecond induction of alpha4 integrin clustering by immobilized chemokines stimulates leukocyte tethering and rolling on endothelial vascular cell adhesion molecule 1 under flow conditions. J Exp Med 2000; 192: 495-506.
- 83 Shamri R, Grabovsky V, Gauguet JM. et al. Lymphocyte arrest requires instantaneous induction of an extended LFA-1 conformation mediated by endotheliumbound chemokines. Nat Immunol 2005; 06: 497-506.
- 84 Hyduk SJ, Chan JR, Duffy ST. et al. Phospholipase C, calcium, and calmodulin are critical for alpha4beta1 integrin affinity up-regulation and monocyte arrest triggered by chemoattractants. Blood 2007; 109: 176-184.
- 85 Ghandour H, Cullere X, Alvarez A. et al. Essential role for Rap1 GTPase and its guanine exchange factor CalDAG-GEFI in LFA-1 but not VLA-4 integrin mediated human T-cell adhesion. Blood 2007; 110: 3682-3690.
- 86 Lafuente E, Boussiotis VA. Rap1 Regulation of RIAM and Cell Adhesion. Methods Enzymol 2005; 407: 345-358.
- 87 Kinashi T, Katagiri K. Regulation of immune cell adhesion and migration by regulator of adhesion and cell polarization enriched in lymphoid tissues. Immunology 2005; 116: 164-171.
- 88 Bos JL. Linking Rap to cell adhesion. Curr Opin Cell Biol 2005; 17: 123-128.
- 89 Lafuente EM, van Puijenbroek AA, Krause M. et al. RIAM, an Ena/VASP and Profilin ligand, interacts with Rap1-GTP and mediates Rap1-induced adhesion. Dev Cell 2004; 07: 585-595.
- 90 Kinashi T, Katagiri K. Regulation of lymphocyte adhesion and migration by the small GTPase Rap1 and its effector molecule, RAPL. Immunol Lett 2004; 93: 1-5.
- 91 Shimonaka M, Katagiri K, Nakayama T. et al. Rap1 translates chemokine signals to integrin activation, cell polarization, and motility across vascular endothelium under flow. J Cell Biol 2003; 161: 417-427.
- 92 Bos JL, de Bruyn K, Enserink J. et al. The role of Rap1 in integrin-mediated cell adhesion. Biochem Soc Trans 2003; 31: 83-86.
- 93 Bos JL, de Rooij J, Reedquist KA. Rap1 signalling: adhering to new models. Nat Rev Mol Cell Biol 2001; 02: 369-377.
- 94 Katagiri K, Hattori M, Minato N. et al. Rap1 is a potent activation signal for leukocyte function-associated antigen 1 distinct from protein kinase C and phosphatidylinositol-3-OH kinase. Mol Cell Biol 2000; 20: 1956-1969.
- 95 Pasvolsky R, Grabovsky V, Giagulli C. et al. RhoA is involved in LFA-1 extension triggered by CXCL12 but not in a novel outside-in LFA-1 activation facilitated by CXCL9. J Immunol 2008; 180: 2815-2823.
- 96 Fagerholm SC, Hilden TJ, Nurmi SM. et al. Specific integrin alpha and beta chain phosphorylations regulate LFA-1 activation through affinity-dependent and -independent mechanisms. J Cell Biol 2005; 171: 705-715.
- 97 Fagerholm SC, Hilden TJ, Gahmberg CG. P marks the spot: site-specific integrin phosphorylation regulates molecular interactions. Trends Biochem Sci 2004; 29: 504-512.
- 98 Fagerholm S, Morrice N, Gahmberg CG. et al. Phosphorylation of the cytoplasmic domain of the integrin CD18 chain by protein kinase C isoforms in leukocytes. J Biol Chem 2002; 277: 1728-1738.
- 99 Hilden TJ, Valmu L, Karkkainen S. et al. Threonine phosphorylation sites in the beta 2 and beta 7 leukocyte integrin polypeptides. J Immunol 2003; 170: 4170-4177.
- 100 Hibbs ML, Jakes S, Stacker SA. et al. The cytoplasmic domain of the integrin lymphocyte functionassociated antigen 1 beta subunit: sites required for binding to intercellular adhesion molecule 1 and the phorbol ester-stimulated phosphorylation site. J Exp Med 1991; 174: 1227-1238.
- 101 Choi EY, Orlova VV, Fagerholm SC. et al. Regulation of LFA-1-dependent inflammatory cell recruitment by Cbl-b and 14-3-3 proteins. Blood 2008; 111: 3607-3614.
- 102 Han J, Lim CJ, Watanabe N. et al. Reconstructing and deconstructing agonist-induced activation of integrin alphaIIbbeta3. Curr Biol 2006; 16: 1796-1806.
- 103 Lee HS, Lim CJ, Puzon-McLaughlin W. et al. RIAM activates integrins by linking talin to Ras GTPase membrane-targeting sequences. J Biol Chem 2009; 284: 5119-5127.
- 104 Tadokoro S, Shattil SJ, Eto K. et al. Talin binding to integrin beta tails: a final common step in integrin activation. Science 2003; 302: 103-106.
- 105 Vinogradova O, Velyvis A, Velyviene A. et al. A structural mechanism of integrin alpha(IIb)beta(3) „inside-out” activation as regulated by its cytoplasmic face. Cell 2002; 110: 587-597.
- 106 Zarbock A, Abram CL, Hundt M. et al. PSGL-1 engagement by E-selectin signals through Src kinase Fgr and ITAM adapters DAP12 and FcR gamma to induce slow leukocyte rolling. J Exp Med 2008; 205: 2339-2347.
- 107 Giagulli C, Ottoboni L, Caveggion E. et al. The Src family kinases Hck and Fgr are dispensable for insideout, chemoattractant-induced signaling regulating beta 2 integrin affinity and valency in neutrophils, but are required for beta 2 integrin-mediated outside-in signaling involved in sustained adhesion. J Immunol 2006; 177: 604-611.
- 108 Gakidis MA, Cullere X, Olson T. et al. Vav GEFs are required for beta2 integrin-dependent functions of neutrophils. J Cell Biol 2004; 166: 273-282.
- 109 Zhang H, Schaff UY, Green CE. et al. Impaired integrin-dependent function in Wiskott-Aldrich syndrome protein-deficient murine and human neutrophils. Immunity 2006; 25: 285-295.
- 110 Moyle M, Foster DL, McGrath DE. et al. A hookworm glycoprotein that inhibits neutrophil function is a ligand of the integrin CD11b/CD18. J Biol Chem 1994; 269: 10008-10015.
- 111 Zhou MY, Lo SK, Bergenfeldt M. et al. In vivo expression of neutrophil inhibitory factor via gene transfer prevents lipopolysaccharide-induced lung neutrophil infiltration and injury by a beta2 integrindependent mechanism. J Clin Invest 1998; 101: 2427-2437.
- 112 Rozdzinski E, Sandros J, van der Flier M. et al. Inhibition of leukocyte-endothelial cell interactions and inflammation by peptides from a bacterial adhesin which mimic coagulation factor X. J Clin Invest 1995; 95: 1078-1085.
- 113 Chavakis T, Preissner KT, Herrmann M. The antiinflammatory activities of Staphylococcus aureus. Trends Immunol 2007; 28: 408-418.
- 114 Bestebroer J, Poppelier MJ, Ulfman LH. et al. Staphylococcal superantigen-like 5 binds PSGL-1 and inhibits P-selectin-mediated neutrophil rolling. Blood 2007; 109: 2936-2943.
- 115 Rhee JS, Santoso S, Herrmann M. et al. New aspects of integrin-mediated leukocyte adhesion in inflammation: regulation by haemostatic factors and bacterial products. Curr Mol Med 2003; 03: 387-92.
- 116 Chavakis T, Hussain M, Kanse SM. et al. Staphylococcus aureus extracellular adherence protein serves as anti-inflammatory factor by inhibiting the recruitment of host leukocytes. Nat Med 2002; 08: 687-693.
- 117 Athanasopoulos AN, Economopoulou M, Orlova VV. et al. The extracellular adherence protein (Eap) of Staphylococcus aureus inhibits wound healing by interfering with host defense and repair mechanisms. Blood 2006; 107: 2720-2727.
- 118 Xie C, Alcaide P, Geisbrecht BV. et al. Suppression of experimental autoimmune encephalomyelitis by extracellular adherence protein of Staphylococcus aureus . J Exp Med 2006; 203: 985-994.
- 119 Hidai C, Zupancic T, Penta K. et al. Cloning and characterization of developmental endothelial locus-1: an embryonic endothelial cell protein that binds the alphavbeta3 integrin receptor. Genes Dev 1998; 12: 21-33.
- 120 Penta K, Varner JA, Liaw L. et al. Del1 induces integrin signaling and angiogenesis by ligation of alphaVbeta3. J Biol Chem 1999; 274: 11101-11109.
- 121 Rezaee M, Penta K, Quertermous T. Del1 mediates VSMC adhesion, migration, and proliferation through interaction with integrin alpha(v)beta(3). Am J Physiol Heart Circ Physiol 2002; 282: H1924-1932.
- 122 Hidai C, Kawana M, Habu K. et al. Overexpression of the Del1 gene causes dendritic branching in the mouse mesentery. Anat Rec A Discov Mol Cell Evol Biol 2007; 287: 1165-1175.
- 123 Aoka Y, Johnson FL, Penta K. et al. The embryonic angiogenic factor Del1 accelerates tumor growth by enhancing vascular formation. Microvasc Res 2002; 64: 148-161.
- 124 Zhong J, Eliceiri B, Stupack D. et al. Neovascularization of ischemic tissues by gene delivery of the extracellular matrix protein Del-1. J Clin Invest 2003; 112: 30-41.
- 125 Ho HK, Jang JJ, Kaji S. et al. Developmental endothelial locus-1 (Del-1), a novel angiogenic protein: its role in ischemia. Circulation 2004; 109: 1314-1319.
- 126 Fan Y, Zhu W, Yang M. et al. Del-1 gene transfer induces cerebral angiogenesis in mice. Brain Res 2008; 1219: 1-7.
- 127 su GP, Mathy JA, Wang Z. et al. Increased rate of hair regrowth in mice with constitutive overexpression of Del1. J Surg Res 2008; 146: 73-80.
- 128 Choi EY, Chavakis E, Czabanka MA. et al. Del-1, an endogenous leukocyte-endothelial adhesion inhibitor, limits inflammatory cell recruitment. Science 2008; 322: 1101-1104.
- 129 Hidai C, Kawana M, Kitano H. et al. Discoidin domain of Del1 protein contributes to its deposition in the extracellular matrix. Cell Tissue Res 2007; 330: 83-95.
- 130 Norling LV, Sampaio AL, Cooper D. et al. Inhibitory control of endothelial galectin-1 on in vitro and in vivo lymphocyte trafficking. Faseb J 2008; 22: 682-690.
- 131 Cooper D, Norling LV, Perretti M. Novel insights into the inhibitory effects of Galectin-1 on neutrophil recruitment under flow. J Leukoc Biol 2008; 83: 1459-1466.
- 132 Tian L, Lappalainen J, Autero M. et al. Shedded neuronal ICAM-5 suppresses T-cell activation. Blood 2008; 111: 3615-3625.
- 133 Zhang H, Casanovas JM, Jin M. et al. An unusual allosteric mobility of the C-terminal helix of a high-affinity alphaL integrin I domain variant bound to ICAM-5. Mol Cell 2008; 31: 432-437.