Key Points
-
Leukocyte adhesion proceeds in a cascade-like fashion, starting with capture and followed by rolling and arrest. In all leukocytes, rapid arrest can be triggered by chemokines, but myeloid cells can also arrest through a chemokine-independent, selectin-dependent pathway.
-
Leukocyte arrest requires integrin activation by inside-out signalling, a process that starts with the dissociation of heterotrimeric Gi-proteins, activation of phospholipase C, which is followed by Ca2+ release from intracellular stores and Ca2+ influx, and activation of the guanine nucleotide exchange factor CALDAG-GEFI (calcium- and diacylglycerol-regulated GEFI). Arrest involves the small GTPases RAP1 and RHOA and other signalling elements that remain to be elucidated, including the cytoskeletal protein(s) that directly interact with leukocyte integrins.
-
After arrest, leukocyte adhesion is strengthened through integrin clustering and outside-in signalling that involves spleen tyrosine kinase (SYK), SRC kinases, phosphoinositide 3-kinase (PI3K), VAV1, VAV2 and VAV3. Monocytes and neutrophils crawl inside the blood vessel before transmigrating.
-
Adherent leukocytes transmigrate through the endothelial monolayer via mechanisms that involve PECAM1 (platelet/endothelial-cell-adhesion molecule), JAM-A (junctional adhesion molecule A), JAM-B and JAM-C, ESAM (endothelial cell-selective adhesion molecule), ICAM1 (intercellular adhesion molecule 1) and ICAM2, VCAM1 (vascular cell-adhesion molecule 1) and CD99. Transmigration proceeds through paracellular and transcellular routes, depending on the stimulus and vascular bed.
-
In the transmigration process, neutrophils and probably other leukocytes alter their cell-surface phenotype, for example by expressing α6β1-integrin, which enables them to migrate through the basement membrane and into adjacent tissues.
Abstract
Neutrophil recruitment, lymphocyte recirculation and monocyte trafficking all require adhesion and transmigration through blood-vessel walls. The traditional three steps of rolling, activation and firm adhesion have recently been augmented and refined. Slow rolling, adhesion strengthening, intraluminal crawling and paracellular and transcellular migration are now recognized as separate, additional steps. In neutrophils, a second activation pathway has been discovered that does not require signalling through G-protein-coupled receptors and the signalling steps leading to integrin activation are beginning to emerge. This Review focuses on new aspects of one of the central paradigms of inflammation and immunity — the leukocyte adhesion cascade.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
£139.00 per year
only £11.58 per issue
Buy this article
- Purchase on SpringerLink
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Dutrochet, H. in Recherches anatomiques et physiologiques sur la structure intime des animaux et des végetaux, et sur leur motilité 1–233 (Bailliere et fils, Paris, 1824). This book contains the first account and drawings of leukocyte transmigration through the wall of microvessels.
Wagner, R. in Erläuterungstafeln zur Physiologie und Entwicklungsgeschichte 1–81 (Leopold Voss, Leipzig, 1839).
Butcher, E. C. Leukocyte–endothelial cell recognition: three (or more) steps to specificity and diversity. Cell 67, 1033–1036 (1991).
Springer, T. A. Traffic signals on endothelium for lymphocyte recirculation and leukocyte emigration. Annu. Rev. Physiol. 57, 827–872 (1995).
Laudanna, C., Kim, J. Y., Constantin, G. & Butcher, E. Rapid leukocyte integrin activation by chemokines. Immunol. Rev. 186, 37–46 (2002).
Kinashi, T. Intracellular signalling controlling integrin activation in lymphocytes. Nature Rev. Immunol. 5, 546–559 (2005).
Imhof, B. A. & Aurrand-Lions, M. Adhesion mechanisms regulating the migration of monocytes. Nature Rev. Immunol. 4, 432–444 (2004).
Muller, W. A. Leukocyte–endothelial-cell interactions in leukocyte transmigration and the inflammatory response. Trends Immunol. 24, 327–334 (2003).
Kansas, G. S. Selectins and their ligands: current concepts and controversies. Blood 88, 3259–3287 (1996).
McEver, R. P. & Cummings, R. D. Role of PSGL-1 binding to selectins in leukocyte recruitment. J. Clin. Invest. 100, 485–491 (1997).
Eriksson, E. E., Xie, X., Werr, J., Thoren, P. & Lindbom, L. Importance of primary capture and L-selectin-dependent secondary capture in leukocyte accumulation in inflammation and atherosclerosis in vivo. J. Exp. Med. 194, 205–218 (2001).
Sperandio, M. et al. P-selectin glycoprotein ligand-1 mediates L-selectin-dependent leukocyte rolling in venules. J. Exp. Med. 197, 1355–1363 (2003).
Rivera-Nieves, J. et al. Critical role of endothelial PSGL-1 in chronic murine ileitis. J. Exp. Med. 203, 907–917 (2006).
da Costa, M. P. et al. P-Selectin glycoprotein ligand-1 is expressed on endothelial cells and mediates monocyte adhesion to activated endothelium. Arterioscler. Thromb. Vasc. Biol. 27, 1023–1029 (2007).
Hidalgo, A., Peired, A. J., Wild, M. K., Vestweber, D. & Frenette, P. S. Complete identification of E-selectin ligands on neutrophils reveals distinct functions of PSGL-1, ESL-1, and CD44. Immunity 26, 477–489 (2007).
Alon, R., Hammer, D. A. & Springer, T. A. Lifetime of the P-selectin-carbohydrate bond and its response to tensile force in hydrodynamic flow. Nature 374, 539–542 (1995).
Finger, E. B. et al. Adhesion through L-selectin requires a threshold hydrodynamic shear. Nature 379, 266–269 (1996).
Lawrence, M. B., Kansas, G. S., Ghosh, S., Kunkel, E. J. & Ley, K. Threshold levels of fluid shear promote leukocyte adhesion through selectins (CD62L, P, E). J. Cell Biol. 136, 717–727 (1997).
Marshall, B. T. et al. Direct observation of catch bonds involving cell-adhesion molecules. Nature 423, 190–193 (2003).
Yago, T., Zarnitsyna, V. I., Klopocki, A. G., McEver, R. P. & Zhu, C. Transport governs flow-enhanced cell tethering through L-selectin at threshold shear. Biophys. J. 92, 330–342 (2007).
Puri, K. D. et al. The role of endothelial PI3Kγ activity in neutrophil trafficking. Blood 106, 150–157 (2005).
Laudanna, C. et al. Sulfatides trigger increase of cytosolic free calcium and enhanced expression of tumor necrosis factor α and interleukin-8 messenger RNA in human neutrophils. Evidence for a role of L-selectin as a signaling molecule. J. Biol. Chem. 269, 4021–4026 (1994).
Yoshida, M. et al. Leukocyte adhesion to vascular endothelium induces E-selectin linkage to the actin cytoskeleton. J. Cell Biol. 133, 445–455 (1996).
Abbal, C. et al. Lipid raft adhesion receptors and Syk regulate selectin-dependent rolling under flow conditions. Blood 108, 3352–3359 (2006).
Simon, S. I., Hu, Y., Vestweber, D. & Smith, C. W. Neutrophil tethering on E-selectin activates β2 integrin binding to ICAM-1 through a mitogen-activated protein kinase signal transduction pathway. J. Immunol. 164, 4348–4358 (2000).
Urzainqui, A. et al. ITAM-based interaction of ERM proteins with Syk mediates signaling by the leukocyte adhesion receptor PSGL-1. Immunity 17, 401–412 (2002). The signalling pathway through PSGL1 involves SYK and ERM proteins. This paper is the first to shed light on non-GPCR-mediated signalling in myeloid cells.
Zarbock, A., Lowell, C. A. & Ley, K. Spleen tyrosine kinase Syk is necessary for E-selectin-induced αLβ2 integrin mediated rolling on intercellular adhesion molecule-1. Immunity 26, 773–783 (2007). This paper identifies an integrin activation pathway that may be as important as activation through GPCRs in neutrophils. PSGL1 engagement activates SYK, which is required for partial activation of LFA1 to allow integrin-mediated rolling.
Berlin, C. et al. α4 integrins mediate lymphocyte attachment and rolling under physiologic flow. Cell 80, 413–422 (1995).
Chan, J. R., Hyduk, S. J. & Cybulsky, M. I. Chemoattractants induce a rapid and transient upregulation of monocyte α4 integrin affinity for vascular cell adhesion molecule 1 which mediates arrest: an early step in the process of emigration. J. Exp. Med. 193, 1149–1158 (2001).
Huo, Y., Hafezi-Moghadam, A. & Ley, K. Role of vascular adhesion molecule-1 (VCAM-1) and fibronectin connecting segment-1 (CS-1) in monocyte adherence on early atherosclerotic lesions. Circ. Res. 87, 153–159 (2000).
Singbartl, K., Thatte, J., Smith, M. L., Day, K. & Ley, K. A CD2-GFP transgenic mouse reveals VLA-4 dependent CD8+ lymphocyte rolling in the inflamed microcirculation. J. Immunol. 166, 7520–7526 (2001).
Kerfoot, S. M. & Kubes, P. Overlapping roles of P-selectin and α4 integrin to recruit leukocytes to the central nervous system in experimental autoimmune encephalomyelitis. J. Immunol. 169, 1000–1006 (2002).
Vajkoczy, P., Laschinger, M. & Engelhardt, B. α4-integrin–VCAM-1 binding mediates G protein-independent capture of encephalitogenic T cell blasts to CNS white matter microvessels. J. Clin. Invest. 108, 557–565 (2001).
Salas, A. et al. Rolling adhesion through an extended conformation of integrin αLβ2 and relation to α I and β I-like domain interaction. Immunity 20, 393–406 (2004).
Chesnutt, B. C. et al. Induction of LFA-1-dependent neutrophil rolling on ICAM-1 by engagement of E-selectin. Microcirculation 13, 99–109 (2006).
Kadono, T., Venturi, G. M., Steeber, D. A. & Tedder, T. F. Leukocyte rolling velocities and migration are optimized by cooperative L-selectin and intercellular adhesion molecule-1 functions. J. Immunol. 169, 4542–4550 (2002).
Sigal, A. et al. The LFA-1 integrin supports rolling adhesions on ICAM-1 under physiological shear flow in a permissive cellular environment. J. Immunol. 165, 442–452 (2000).
Astrof, N. S., Salas, A., Shimaoka, M., Chen, J. & Springer, T. A. Importance of force linkage in mechanochemistry of adhesion receptors. Biochemistry 45, 15020–15028 (2006).
Kunkel, E. J. & Ley, K. Distinct phenotype of E-selectin deficient mice. E-selectin is required for slow leukocyte rolling in vivo. Circ. Res. 79, 1196–1204 (1996).
Jung, U. et al. Transit time of leukocytes rolling through venules controls cytokine-induced inflammatory cell recruitment in vivo. J. Clin. Invest. 102, 1526–1533 (1998).
Dunne, J. L., Ballantyne, C. M., Beaudet, A. L. & Ley, K. Control of leukocyte rolling velocity in TNF-α induced inflammation by LFA-1 and Mac-1. Blood 99, 336–341 (2002).
Lo, S. K. et al. Endothelial-leukocyte adhesion molecule-1 stimulates the adhesive activity of leukocyte integrin CR3 (CD11b/CD18, Mac-1, αMβ2) on human neutrophils. J. Exp. Med. 173, 1493–1500 (1991).
Campbell, J. J., Qin, S. X., Bacon, K. B., MacKay, C. R. & Butcher, E. C. Biology of chemokine and classical chemoattractant receptors. Differential requirements for adhesion-triggering versus chemotactic responses in lymphoid cells. J. Cell Biol. 134, 255–266 (1996).
Campbell, J. J. et al. Chemokines and the arrest of lymphocytes rolling under flow conditions. Science 279, 381–384 (1998). Reference 43 foreshadows the special requirements for the arrest of lymphocytes under flow and distinguishes arrest from chemotaxis. A more detailed account of the chemokines involved in arrest can be found in reference 44.
Middleton, J. et al. Transcytosis and surface presentation of IL-8 by venular endothelial cells. Cell 91, 385–395 (1997).
von Hundelshausen, P. et al. RANTES deposition by platelets triggers monocyte arrest on inflamed and atherosclerotic endothelium. Circulation 103, 1772–1777 (2001).
Huo, Y. et al. Circulating activated platelets exacerbate atherosclerosis in mice deficient in apolipoprotein E. Nature Med. 9, 61–67 (2003).
von Hundelshausen, P. et al. Heterophilic interactions of platelet factor 4 and RANTES promote monocyte arrest on endothelium. Blood 105, 924–930 (2005).
Johnson, Z., Proudfoot, A. E. & Handel, T. M. Interaction of chemokines and glycosaminoglycans: a new twist in the regulation of chemokine function with opportunities for therapeutic intervention. Cytokine Growth Factor Rev. 16, 625–636 (2005).
Constantin, G. et al. Chemokines trigger immediate β2 integrin affinity and mobility changes: differential regulation and roles in lymphocyte arrest under flow. Immunity 13, 759–769 (2000).
Shamri, R. et al. Lymphocyte arrest requires instantaneous induction of an extended LFA-1 conformation mediated by endothelium-bound chemokines. Nature Immunol. 6, 497–506 (2005).
D'Ambrosio, D. et al. Quantitative differences in chemokine receptor engagement generate diversity in integrin-dependent lymphocyte adhesion. J. Immunol. 169, 2303–2312 (2002).
Giagulli, C. et al. RhoA and ζ PKC control distinct modalities of LFA-1 activation by chemokines: critical role of LFA-1 affinity triggering in lymphocyte in vivo homing. Immunity 20, 25–35 (2004).
Kim, M., Carman, C. V. & Springer, T. A. Bidirectional transmembrane signaling by cytoplasmic domain separation in integrins. Science 301, 1720–1725 (2003). Fluorescence resonance energy transfer was used to demonstrate in living cells that separation of the cytoplasmic tails of LFA1 (the α L and β 2 cytoplasmic tails) results in increased adhesive function and binding of a reporter antibody for the extended conformation.
Arnaout, M. A., Mahalingam, B. & Xiong, J. P. Integrin structure, allostery, and bidirectional signaling. Annu. Rev. Cell Dev. Biol. 21, 381–410 (2005).
Chigaev, A. et al. α4β1 integrin affinity changes govern cell adhesion. J. Biol. Chem. 278, 38174–38182 (2003).
Hyduk, S. J. et al. Phospholipase C, calcium and calmodulin are critical for α4β1 integrin affinity up-regulation and monocyte arrest triggered by chemoattractants. Blood 109, 176–184 (2007). Although many signalling pathways are activated by GPCR signalling, this study shows that PLC signalling is required for integrin activation in monocytes.
Crittenden, J. R. et al. CalDAG-GEFI integrates signaling for platelet aggregation and thrombus formation. Nature Med. 10, 982–986 (2004).
Nombela-Arrieta, C. et al. Differential requirements for DOCK2 and phosphoinositide-3-kinase γ during T and B lymphocyte homing. Immunity 21, 429–441 (2004).
Gakidis, M. A. et al. Vav GEFs are required for β2 integrin-dependent functions of neutrophils. J. Cell Biol. 166, 273–282 (2004).
Pasvolsky, R. et al. A LAD-III syndrome is associated with defective expression of the Rap-1 activator CalDAG-GEFI in lymphocytes, neutrophils, and platelets. J. Exp. Med. 204, 1571–1582 (2007).
Bergmeier, W. et al. Mice lacking the signaling molecule CalDAG-GEFI represent a model for leukocyte adhesion deficiency type III. J. Clin. Invest. 117, 1699–1707 (2007).
Vielkind, S., Gallagher-Gambarelli, M., Gomez, M., Hinton, H. J. & Cantrell, D. A. Integrin regulation by RhoA in thymocytes. J. Immunol. 175, 350–357 (2005).
Wittchen, E. S., van Buul, J. D., Burridge, K. & Worthylake, R. A. Trading spaces: Rap, Rac, and Rho as architects of transendothelial migration. Curr. Opin. Hematol. 12, 14–21 (2005).
Tadokoro, S. et al. Talin binding to integrin β tails: a final common step in integrin activation. Science 302, 103–106 (2003). This study demonstrated that knockdown of talin-1 inhibits affinity up-regulation of multiple integrins, including α IIb β 3 -integrin, α v β 3 -integrin and α 5 β 1 -integrin.
Wegener, K. L. et al. Structural basis of integrin activation by talin. Cell 128, 171–182 (2007).
Sampath, R., Gallagher, P. J. & Pavalko, F. M. Cytoskeletal interactions with the leukocyte integrin β2 cytoplasmic tail. Activation-dependent regulation of associations with talin and α-actinin. J. Biol. Chem. 273, 33588–33594 (1998).
Jones, S. L., Wang, J., Turck, C. W. & Brown, E. J. A role for the actin-bundling protein L-plastin in the regulation of leukocyte integrin function. Proc. Natl Acad. Sci. USA 95, 9331–9336 (1998).
D'Ambrosio, D., Lecca, P., Constantin, G., Priami, C. & Laudanna, C. Concurrency in leukocyte vascular recognition: developing the tools for a predictive computer model. Trends Immunol. 25, 411–416 (2004).
Giagulli, C. et al. The Src family kinases Hck and Fgr are dispensable for inside-out, chemoattractant-induced signaling regulating β2 integrin affinity and valency in neutrophils, but are required for β2 integrin-mediated outside-in signaling involved in sustained adhesion. J. Immunol. 177, 604–611 (2006).
Shattil, S. J. Integrins and Src: dynamic duo of adhesion signaling. Trends Cell Biol. 15, 399–403 (2005).
Liu, S. et al. A fragment of paxillin binds the α4 integrin cytoplasmic domain (tail) and selectively inhibits α4-mediated cell migration. J. Biol. Chem. 277, 20887–20894 (2002).
Smith, D. F. et al. Leukocyte phoshoinositide-3-kinase γ is required for chemokine-induced sustained adhesion under flow in vivo. J. Leukoc. Biol. 80, 1491–1499 (2006).
Liu, S. et al. Binding of paxillin to α4 integrins modifies integrin-dependent biological responses. Nature 402, 676–681 (1999).
Han, J. et al. Phosphorylation of the integrin α4 cytoplasmic domain regulates paxillin binding. J. Biol. Chem. 276, 40903–40909 (2001).
Hyduk, S. J., Oh, J., Xiao, H., Chen, M. & Cybulsky, M. I. Paxillin selectively associates with constitutive and chemoattractant-induced high-affinity α4β1 integrins: implications for integrin signaling. Blood 104, 2818–2824 (2004).
Goldfinger, L. E., Han, J., Kiosses, W. B., Howe, A. K. & Ginsberg, M. H. Spatial restriction of α4 integrin phosphorylation regulates lamellipodial stability and α4β1-dependent cell migration. J. Cell Biol. 162, 731–741 (2003).
Nishiya, N., Kiosses, W. B., Han, J. & Ginsberg, M. H. An α4 integrin–paxillin–Arf-GAP complex restricts Rac activation to the leading edge of migrating cells. Nature Cell Biol. 7, 343–352 (2005).
Feral, C. C. et al. Blocking the α4 integrin-paxillin interaction selectively impairs mononuclear leukocyte recruitment to an inflammatory site. J. Clin. Invest. 116, 715–723 (2006).
Nandi, A., Estess, P. & Siegelman, M. Bimolecular complex between rolling and firm adhesion receptors required for cell arrest: CD44 association with VLA-4 in T cell extravasation. Immunity 20, 455–465 (2004).
Schenkel, A. R., Mamdouh, Z. & Muller, W. A. Locomotion of monocytes on endothelium is a critical step during extravasation. Nature Immunol. 5, 393–400 (2004).
Phillipson, M. et al. Intraluminal crawling of neutrophils to emigration sites: a molecularly distinct process from adhesion in the recruitment cascade. J. Exp. Med. 203, 2569–2575 (2006). Reference 81 identifies crawling on the endothelium as a crucial step in the adhesion cascade, at least for monocytes. Reference 82 confirms this observation in vivo and extends it to neutrophils.
Cinamon, G., Shinder, V., Shamri, R. & Alon, R. Chemoattractant signals and β2 integrin occupancy at apical endothelial contacts combine with shear stress signals to promote transendothelial neutrophil migration. J. Immunol. 173, 7282–7291 (2004).
Barreiro, O. et al. Dynamic interaction of VCAM-1 and ICAM-1 with moesin and ezrin in a novel endothelial docking structure for adherent leukocytes. J. Cell Biol. 157, 1233–1245 (2002).
Carman, C. V. & Springer, T. A. A transmigratory cup in leukocyte diapedesis both through individual vascular endothelial cells and between them. J. Cell Biol. 167, 377–388 (2004). Reference 84 shows that the endothelial docking structure is enriched for the adhesion molecules VCAM1 and ICAM1. Docking precedes transmigration, as shown in reference 85.
Greenwood, J. et al. Intracellular domain of brain endothelial intercellular adhesion molecule-1 is essential for T lymphocyte-mediated signaling and migration. J. Immunol. 171, 2099–2108 (2003).
Millan, J. & Ridley, A. J. Rho GTPases and leucocyte-induced endothelial remodelling. Biochem. J. 385, 329–337 (2005).
Huang, A. J. et al. Endothelial cell cytosolic free calcium regulates neutrophil migration across monolayers of endothelial cells. J. Cell Biol. 120, 1371–1380 (1993).
Shaw, S. K., Bamba, P. S., Perkins, B. N. & Luscinskas, F. W. Real-time imaging of vascular endothelial-cadherin during leukocyte transmigration across endothelium. J. Immunol. 167, 2323–2330 (2001).
Vestweber, D. Regulation of endothelial cell contacts during leukocyte extravasation. Curr. Opin. Cell Biol. 14, 587–593 (2002).
Nourshargh, S., Krombach, F. & Dejana, E. The role of JAM-A and PECAM-1 in modulating leukocyte infiltration in inflamed and ischemic tissues. J. Leukoc. Biol. 80, 714–718 (2006).
Wegmann, F. et al. ESAM supports neutrophil extravasation, activation of Rho, and VEGF-induced vascular permeability. J. Exp. Med. 203, 1671–1677 (2006).
Reymond, N. et al. DNAM-1 and PVR regulate monocyte migration through endothelial junctions. J. Exp. Med. 199, 1331–1341 (2004).
Salmi, M. & Jalkanen, S. Cell-surface enzymes in control of leukocyte trafficking. Nature Rev. Immunol. 5, 760–771 (2005).
Liu, L. et al. LSP1 is an endothelial gatekeeper of leukocyte transendothelial migration. J. Exp. Med. 201, 409–418 (2005).
Mamdouh, Z., Chen, X., Pierini, L. M., Maxfield, F. R. & Muller, W. A. Targeted recycling of PECAM from endothelial surface-connected compartments during diapedesis. Nature 421, 748–753 (2003). The first demonstration of a pool of intracellular PECAM1 in endothelial cells and its recycling and significant role in transendothelial cell migration.
Dejana, E. Endothelial cell–cell junctions: happy together. Nature Rev. Mol. Cell Biol. 5, 261–270 (2004).
Schenkel, A. R., Mamdouh, Z., Chen, X., Liebman, R. M. & Muller, W. A. CD99 plays a major role in the migration of monocytes through endothelial junctions. Nature Immunol. 3, 143–150 (2002).
Lou, O., Alcaide, P., Luscinskas, F. W. & Muller, W. A. CD99 is a key mediator of the transendothelial migration of neutrophils. J. Immunol. 178, 1136–1143 (2007).
Feng, D., Nagy, J. A., Pyne, K., Dvorak, H. F. & Dvorak, A. M. Neutrophils emigrate from venules by a transendothelial cell pathway in response to fMLP. J. Exp. Med. 187, 903–915 (1998). The first convincing report on the ability of leukocytes to penetrate endothelial cells and pericytes by the transcellular route in vivo , as investigated by detailed analysis of tissue serial sections by electron microscopy.
Engelhardt, B. & Wolburg, H. Mini-review: Transendothelial migration of leukocytes: through the front door or around the side of the house? Eur. J. Immunol. 34, 2955–2963 (2004).
Millan, J. et al. Lymphocyte transcellular migration occurs through recruitment of endothelial ICAM-1 to caveola- and F-actin-rich domains. Nature Cell Biol. 8, 113–123 (2006).
Nieminen, M. et al. Vimentin function in lymphocyte adhesion and transcellular migration. Nature Cell Biol. 8, 156–162 (2006).
Dvorak, A. M. & Feng, D. The vesiculo-vacuolar organelle (VVO). A new endothelial cell permeability organelle. J. Histochem. Cytochem. 49, 419–432 (2001).
Hallmann, R. et al. Expression and function of laminins in the embryonic and mature vasculature. Physiol Rev. 85, 979–1000 (2005).
Wang, S. et al. Venular basement membranes contain specific matrix protein low expression regions that act as exit points for emigrating neutrophils. J. Exp. Med. 203, 1519–1532 (2006). This paper reports on the existence of regions within the endothelial-cell basement membrane where expression of certain extracellular-matrix proteins is low and they are therefore more permissive to emigrating neutrophils.
Sixt, M. et al. Endothelial cell laminin isoforms, laminins 8 and 10, play decisive roles in T cell recruitment across the blood-brain barrier in experimental autoimmune encephalomyelitis. J. Cell Biol. 153, 933–946 (2001).
Miyasaka, M. & Tanaka, T. Lymphocyte trafficking across high endothelial venules: dogmas and enigmas. Nature Rev. Immunol. 4, 360–370 (2004).
Nourshargh, S. & Marelli-Berg, F. M. Transmigration through venular walls: a key regulator of leukocyte phenotype and function. Trends Immunol. 26, 157–165 (2005).
Newman, P. J. & Newman, D. K. Signal transduction pathways mediated by PECAM-1: new roles for an old molecule in platelet and vascular cell biology. Arterioscler. Thromb. Vasc. Biol. 23, 953–964 (2003).
Dangerfield, J., Larbi, K. Y., Huang, M. T., Dewar, A. & Nourshargh, S. PECAM-1 (CD31) homophilic interaction up-regulates α6β1 on transmigrated neutrophils in vivo and plays a functional role in the ability of α6 integrins to mediate leukocyte migration through the perivascular basement membrane. J. Exp. Med. 196, 1201–1211 (2002).
Werr, J., Eriksson, E. E., Hedqvist, P. & Lindbom, L. Engagement of β2 integrins induces surface expression of β1 integrin receptors in human neutrophils. J. Leukoc. Biol. 68, 553–560 (2000). References 111 and 112 identify a mechanism by which transendothelial migration enables neutrophils to engage molecules of the basement membrane through the surface expression of α 2 β 1 -integrin, α 6 β 1 -integrin and other integrins.
Adair-Kirk, T. L. et al. A site on laminin α5, AQARSAASKVKVSMKF, induces inflammatory cell production of matrix metalloproteinase-9 and chemotaxis. J. Immunol. 171, 398–406 (2003).
Cepinskas, G., Sandig, M. & Kvietys, P. R. PAF-induced elastase-dependent neutrophil transendothelial migration is associated with the mobilization of elastase to the neutrophil surface and localization to the migrating front. J. Cell Sci. 112, 1937–1945 (1999).
Wang, S., Dangerfield, J. P., Young, R. E. & Nourshargh, S. PECAM-1, α6 integrins and neutrophil elastase cooperate in mediating neutrophil transmigration. J. Cell Sci. 118, 2067–2076 (2005).
Carman, C. V. & Springer, T. A. Integrin avidity regulation: are changes in affinity and conformation underemphasized? Curr. Opin. Cell Biol. 15, 547–556 (2003).
Bazzoni, G. & Hemler, M. E. Are changes in integrin affinity and conformation overemphasized? Trends Biochem. Sci. 23, 30–34 (1998).
Maly, P. et al. The α(1,3)fucosyltransferase Fuc-TVII controls leukocyte trafficking through an essential role in L-, E-, and P-selectin ligand biosynthesis. Cell 86, 643–653 (1996). In this paper, fucosyltransferase VII is identified as the defining enzyme of selectin ligands. Its regulation determines whether selectin ligands, such as PSGL1, can actually bind their target receptors.
Ellies, L. G. et al. Sialyltransferase specificity in selectin ligand formation. Blood 100, 3618–3625 (2002).
Ellies, L. G. et al. Core 2 oligosaccharide biosynthesis distinguishes between selectin ligands essential for leukocyte homing and inflammation. Immunity 9, 881–890 (1998).
Moore, K. L. The biology and enzymology of protein tyrosine O-sulfation. J. Biol. Chem. 278, 24243–24246 (2003).
Weninger, W. et al. Specialized contributions by α(1,3)-fucosyltransferase-IV and FucT-VII during leukocyte rolling in dermal microvessels. Immunity 12, 665–676 (2000).
Rosen, S. D. Ligands for L-selectin: homing, inflammation, and beyond. Annu. Rev. Immunol. 22, 129–156 (2004).
Staunton, D. E., Dustin, M. L. & Springer, T. A. Functional cloning of ICAM-2, a cell adhesion ligand for LFA-1 homologous to ICAM-1. Nature 339, 61–64 (1989).
Xie, J. L. et al. Intercellular adhesion molecule-2 (CD102) binds to the leukocyte integrin CD11b/CD18 through the A domain. J. Immunol. 155, 3619–3628 (1995).
Bixel, M. G. et al. A CD99-related antigen on endothelial cells mediates neutrophil, but not lymphocyte extravasation in vivo. Blood 109, 5327–5336 (2007).
Duncan, G. S. et al. Genetic evidence for functional redundancy of platelet/endothelial cell adhesion molecule-1 (PECAM-1): CD31-deficient mice reveal PECAM-1-dependent and PECAM-1-independent functions. J. Immunol. 162, 3022–3030 (1999).
Thompson, R. D. et al. Platelet-endothelial cell adhesion molecule-1 (PECAM-1)-deficient mice demonstrate a transient and cytokine-specific role for PECAM-1 in leukocyte migration through the perivascular basement membrane. Blood 97, 1854–1860 (2001).
Graesser, D. et al. Altered vascular permeability and early onset of experimental autoimmune encephalomyelitis in PECAM-1-deficient mice. J. Clin. Invest. 109, 383–392 (2002).
Schenkel, A. R., Chew, T. W. & Muller, W. A. Platelet endothelial cell adhesion molecule deficiency or blockade significantly reduces leukocyte emigration in a majority of mouse strains. J. Immunol. 173, 6403–6408 (2004).
Tada, Y. et al. Acceleration of the onset of collagen-induced arthritis by a deficiency of platelet endothelial cell adhesion molecule 1. Arthritis Rheum. 48, 3280–3290 (2003).
Gerwin, N. et al. Prolonged eosinophil accumulation in allergic lung interstitium of ICAM-2-deficient mice results in extended hyperresponsiveness. Immunity 10, 9–19 (1999).
Huang, M. T. et al. ICAM-2 mediates neutrophil transmigration in vivo: evidence for stimulus-specificity and a role in PECAM-1-independent transmigration. Blood 107, 4721–4727 (2006).
Corada, M. et al. Junctional adhesion molecule-A-deficient polymorphonuclear cells show reduced diapedesis in peritonitis and heart ischemia-reperfusion injury. Proc. Natl Acad. Sci. USA 102, 10634–10639 (2005).
Khandoga, A. et al. Junctional adhesion molecule-A deficiency increases hepatic ischemia-reperfusion injury despite reduction of neutrophil transendothelial migration. Blood 106, 725–733 (2005).
Acknowledgements
K.L. is funded by the National Institutes of Health. S.N. is funded by the Wellcome Trust UK and the British Heart Foundation. We wish to thank M.-B. Voisin for his contribution to Fig. 3. M.C. is a Career Investigator of the Heart and Stroke Foundation of Ontario and is funded by the Canadian Institutes of Health Research.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Competing interests
The authors declare no competing financial interests.
Supplementary information
Related links
Glossary
- Combinatorial specificity
-
Specificity achieved in a sequential cascade. If there are 3 rolling molecules, 15 chemokines and 2 integrins, theoretically, 90 (3 × 15 × 2) specificities are possible.
- Slow rolling
-
Rolling mediated by selectins (usually E-selectin) and integrins (usually LFA1), most commonly seen in neutrophils. Typical velocity is under 5 μm per second.
- Shear stress
-
Shear stress (dyn per cm2) is the force exerted by the flowing blood (dyn) on each unit of area of endothelial surface (cm2).
- Catch bond
-
A molecular bond that becomes stronger as pulling force is applied to it. By contrast, a slip bond becomes weaker.
- G-protein-coupled receptor
-
(GPCR). A receptor that is composed of seven membrane-spanning helical segments, which are connected by extracellular and intracellular loops. These receptors associate with G proteins, which are a family of trimeric intracellular-signalling proteins with specific β- and γ-chains, and one of several α-chains.
- Inside-out signalling
-
The process by which intracellular signalling mechanisms result in the activation of a cell-surface receptor. By contrast, outside-in signalling is the process by which ligation of a cell-surface receptor activates signalling pathways inside the cell.
- LIM domains
-
LIM domains are named after their discovery in developmentally regulated transcription factors LIN11, ISL1 and MEC3. Each LIM domain consists of two tandem zinc fingers separated by two amino acids. LIM domains mediate protein–protein interactions and are frequently found in multiples.
- Pericytes
-
Pericytes are cells that are ∼150–200 μm long and ∼10–25 μm wide. They express smooth-muscle-cell α-actin and form a discontinuous network wrapped around endothelial cells of almost all post-capillary venules, and exhibit large gaps between adjacent cells.
- Vesiculo-vacuolar organelles
-
(VVOs). Focal clusters of vesicles and vacuoles in the form of 'bunches of grapes' within the cytoplasm of microvascular endothelial cells. In response to VEGF or histamine they can provide a direct link between the vascular lumen and extravascular space. This is thought to be part of the mechanism behind increased vascular permeability.
Rights and permissions
About this article
Cite this article
Ley, K., Laudanna, C., Cybulsky, M. et al. Getting to the site of inflammation: the leukocyte adhesion cascade updated. Nat Rev Immunol 7, 678–689 (2007). https://doi.org/10.1038/nri2156
Issue Date:
DOI: https://doi.org/10.1038/nri2156