Immune responses depend on the ability of leukocytes to move from the circulation into tissues. Leukocyte extravasation is guided and controlled by endothelial cells that capture circulating leukocytes and open a path for diapedesis.
Regulation of integrin-mediated adhesion controls the slowing down of leukocyte rolling, leukocyte arrest, crawling and migration through the blood vessel wall. Each of these cellular functions is tightly regulated and depends on different extracellular factors and binding partners with varying signalling requirements.
A central step in the diapedesis process involves a mechanism that stimulates the opening of endothelial cell junctions, which depends on regulating the function of VE-cadherin. An alternative, although less common, pathway is the transcellular route through endothelial cells.
The diapedesis process involves many functions of leukocytes and endothelial cells, from stopping intraluminal crawling at suitable exit sites to loosening of endothelial cell contacts, preventing plasma leakage, extending the membrane surface area at endothelial cell junctions, active leukocyte migration through the junctional cleft, preventing reverse transmigration and sealing of the junction after diapedesis.
After crossing the endothelial barrier, leukocytes crawl along pericytes to reach preferential sites of exit through the basement membrane that are characterized by low levels of expression of certain protein components.
Understanding the process of leukocyte diapedesis in more detail will help to identify molecular targets, to interfere with various inflammatory processes.
Immune responses depend on the ability of leukocytes to move from the circulation into tissue. This is enabled by mechanisms that guide leukocytes to the right exit sites and allow them to cross the barrier of the blood vessel wall. This process is regulated by a concerted action between endothelial cells and leukocytes, whereby endothelial cells activate leukocytes and direct them to extravasation sites, and leukocytes in turn instruct endothelial cells to open a path for transmigration. This Review focuses on recently described mechanisms that control and open exit routes for leukocytes through the endothelial barrier.
Subscribe to Journal
Get full journal access for 1 year
only $21.58 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
McEver, R. P. Selectins: initiators of of leukocyte adhesion and signalling at the vascular wall. Cardiovasc. Res. 107, 331–339 (2015).
Vestweber, D. & Blanks, J. E. Mechanisms that regulate the function of the selectins and their ligands. Physiol. Rev. 79, 181–213 (1999).
Sundd, P. et al. 'Slings' enable neutrophil rolling at high shear. Nature 488, 399–403 (2012).
Alon, R. & Feigelson, S. W. Chemokine-triggered leukocyte arrest: force-regulated bi-directional integrin activation in quantal adhesive contacts. Curr. Opin. Cell Biol. 24, 670–676 (2012).
van Buul, J. D., Kanters, E. & Hordijk, P. L. Endothelial signaling by Ig-like cell adhesion molecules. Arterioscler. Thromb. Vasc. Biol. 27, 1870–1876 (2007).
Muller, W. A. The role of PECAM-1 (CD31) in leukocyte emigration: studies in vitro and in vivo. J. Leukoc. Biol. 57, 523–528 (1995).
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).
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. Nat. Immunol. 3, 143–150 (2002). This is the first study to show that paracellular diapedesis is mediated by sequential steps.
Reymond, N. et al. DNAM-1 and PVR regulate monocyte migration through endothelial junctions. J. Exp. Med. 199, 1331–1341 (2004).
Nourshargh, S., Hordijk, P. L. & Sixt, M. Breaching multiple barriers: leukocyte motility through venular walls and the interstitium. Nat. Rev. Mol. Cell Biol. 11, 366–378 (2010).
Campbell, I. D. & Humphries, M. J. Integrin structure, activation, and interactions. Cold Spring Harb. Perspect. Biol. 3, a004994 (2011).
Herter, J. & Zarbock, A. Integrin regulation during leukocyte recruitment. J. Immunol. 190, 4451–4457 (2013).
Luo, B. H., Carman, C. V. & Springer, T. A. Structural basis of integrin regulation and signaling. Annu. Rev. Immunol. 25, 619–647 (2007).
Moser, M., Legate, K. R., Zent, R. & Fässler, R. The tail of integrins, talin, and kindlins. Science 324, 895–899 (2009).
Abram, C. L. & Lowell, C. A. The ins and outs of leukocyte integrin signaling. Annu. Rev, Immunol. 27, 399–362 (2009).
Zarbock, A., Ley, K., McEver, R. P. & Hidalgo, A. Leukocyte ligands for endothelial selectins: specialized glycoconjugates that mediate rolling and signaling under flow. Blood 118, 6743–6751 (2011).
Kuwano, Y., Spelten, O., Zhang, H., Ley, K. & Zarbock, A. Rolling on E- or P-selectin induces the extended but not high-affinity conformation of LFA-1 in neutrophils. Blood 116, 617–624 (2010).
Lefort, C. T. et al. Distinct roles for talin-1 and kindlin-3 in LFA-1 extension and affinity regulation. Blood 119, 4275–4282 (2012). This study shows that activation of the integrin LFA1 to the intermediate-affinity conformation, which supports slow leukocyte rolling, requires only the binding of talin, whereas activation to the high-affinity conformation requires binding of talin and kindlin 3.
Yago, T. et al. Blocking neutrophil integrin activation prevents ischemia-reperfusion injury. J. Exp. Med. 212, 1267–1281 (2015).
Choi, E. Y. et al. Del-1, an endogenous leukocyte-endothelial adhesion inhibitor, limits inflammatory cell recruitment. Science 322, 1101–1104 (2008).
Choi, E. Y. et al. Developmental endothelial locus-1 is a homeostatic factor in the central nervous system limiting neuroinflammation and demyelination. Mol. Psychiatry 20, 880–888 (2014).
Kempf, T. et al. GDF-15 is an inhibitor of leukocyte integrin activation required for survival after myocardial infarction in mice. Nat. Med. 17, 581–588 (2011).
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).
Halai, K., Whiteford, J., Ma, B., Nourshargh, S. & Woodfin, A. ICAM-2 facilitates luminal interactions between neutrophils and endothelial cells in vivo. J. Cell Sci. 127, 620–629 (2014).
Auffray, C. et al. Monitoring of blood vessels and tissues by a population of monocytes with patrolling behavior. Science 317, 666–670 (2007).
Sumagin, R., Prizant, H., Lomakina, E., Waugh, R. E. & Sarelius, I. H. LFA-1 and Mac-1 define characteristically different intralumenal crawling and emigration patterns for monocytes and neutrophils in situ. J. Immunol. 185, 7057–7066 (2010).
Carlin, L. M. et al. Nr4a1-dependent Ly6C(low) monocytes monitor endothelial cells and orchestrate their disposal. Cell 153, 362–375 (2013).
Bartholomäus, I. et al. Effector T cell interactions with meningeal vascular structures in nascent autoimmune CNS lesions. Nature 462, 94–98 (2009).
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).
Carman, C. V. et al. Transcellular diapedesis is initiated by invasive podosomes. Immunity 26, 784–797 (2007).
van Buul, J. D. et al. RhoG regulates endothelial apical cup assembly downstream from ICAM1 engagement and is involved in leukocyte trans-endothelial migration. J. Cell Biol. 178, 1279–1293 (2007).
Shaw, S. K. et al. Coordinated redistribution of leukocyte LFA-1 and endothelial cell ICAM-1 accompany neutrophil transmigration. J. Exp. Med. 200, 1571–1580 (2004).
Yang, L. et al. Endothelial cell cortactin coordinates intercellular adhesion molecule-1 clustering and actin cytoskeleton remodeling during polymorphonuclear leukocyte adhesion and transmigration. J. Immunol. 177, 6440–6449 (2006).
Yang, L., Kowalski, J. R., Zhan, X., Thomas, S. M. & Luscinskas, F. W. Endothelial cell cortactin phosphorylation by Src contributes to polymorphonuclear leukocyte transmigration in vitro. Circ. Res. 98, 394–402 (2006).
Schnoor, M. et al. Cortactin deficiency is associated with reduced neutrophil recruitment but increased vascular permeability in vivo. J. Exp. Med. 208, 1721–1735 (2011).
Baluk, P., Bolton, P., Hirata, A., Thurston, G. & McDonald, D. M. Endothelial gaps and adherent leukocytes in allergen-induced early- and late-phase plasma leakage in rat airways. Am. J. Pathol. 152, 1463–1476 (1998).
He, P. Leukocyte/endothelium intercations and microvessel permeability: coupled or uncoupled? Cardiovasc. Res. 87, 281–290 (2010).
Woodfin, A. et al. The junctional adhesion molecule JAM-C regulates polarized transendothelial migration of neutrophils in vivo. Nat. Immunol. 12, 761–769 (2011). This paper visualizes for the first time leukocyte extravasation in vivo by 3D live imaging. It determines the numbers of paracellular and transcellular diapedesing neutrophils and demonstrates that the lack of JAMC leads to reverse transmigration of neutrophils.
Martin-Padura, I. et al. Junctional adhesion molecule, a novel member of the immunoglobulin superfamily that distributes at intercellular junctions and modulates monocyte transmigration. J. Cell Biol. 142, 117–127 (1998).
Ostermann, G., Weber, K. S., Zernecke, A., Schroder, A. & Weber, C. JAM-1 is a ligand of the β2 integrin LFA-1 involved in transendothelial migration of leukocytes. Nat. Immunol. 3, 151–158 (2002).
Scott, D. W. et al. N-glycosylation controls the function of the junctional adhesion molecule-A. Mol. Biol. Cell 26, 3205–3214 (2015).
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).
Woodfin, A. et al. JAM-A mediates neutrophil transmigration in a stimulus-specific manner in vivo: evidence for sequential roles for JAM-A and PECAM-1 in neutrophil transmigration. Blood 110, 1848–1856 (2007). This study shows for the first time that two adhesion receptors function sequentially during neutrophil diapedesis in postcapillary venules.
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).
Schmitt, M. M. et al. Endothelial junctional adhesion molecule-a guides monocytes into flow-dependent predilection sites of atherosclerosis. Circulation 129, 66–76 (2014).
Zen, K. et al. JAM-C is a component of desmosomes and a ligand for CD11b/CD18-mediated neutrophil transepithelial migration. Mol. Biol. Cell 15, 3926–3937 (2004).
Aurrand-Lions, M. et al. Junctional adhesion molecule-C regulates the early influx of leukocytes into tissues during inflammation. J. Immunol. 174, 6406–6415 (2005).
Colom, B. et al.Leukotriene B4-neutrophil elastase axis drives neutrophil reverse transendothelial cell migration in vivo. Immunity 42, 1075–1086 (2015).
Nasdala, I. et al. A transmembrane tight junction protein selectively expressed on endothelial cells and platelets. J. Biol. Chem. 277, 16294–16303 (2002).
Conway, D. E. et al. Fluid shear stress on endothelial cells modulates mechanical tension across VE-cadherin and PECAM-1. Curr. Biol. 23, 1024–1030 (2013).
Conway, D. E. & Schwartz, M. A. Mechanotransduction of shear stress occurs through changes in VE-cadherin and PECAM-1 tension: Implications for cell migration. Cell Adh. Migr. http://dx.doi.org/10.4161/19336918.2014.968498 (2014).
Liao, F. et al. Migration of monocytes across endothelium and passage through extracellular matrix involve separate molecular domains of PECAM-1. J. Exp. Med. 182, 1337–1343 (1995).
Wakelin, M. W. et al. 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, 229–239 (1996).
Liao, F., Ali, J., Greene, T. & Muller, W. A. Soluble domain 1 of platelet-endothelial cell adhesion molecule (PECAM) is sufficient to block transendothelial migration in vitro and in vivo. J. Exp. Med. 185, 1349–1357 (1997).
Thompson, R. D. et al. Divergent effects of platelet-endothelial cell adhesion molecule-1 and β3 integrin blockade on leukocyte transmigration in vivo. J. Immunol. 165, 426–434 (2000).
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).
Woodfin, A. et al. Endothelial cell activation leads to neutrophil transmigration as supported by the sequential roles of ICAM-2, JAM-A and PECAM-1. Blood 113, 6246–6257 (2009).
Bixel, G. et al. Mouse CD99 participates in T cell recruitment into inflamed skin. Blood 104, 3205–3213 (2004).
Dufour, E. M., Deroche, A., Bae, Y. & Muller, W. A. CD99 is essential for leukocyte diapedesis in vivo. Cell Commun. Adhes. 15, 351–363 (2008).
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).
Schenkel, A. R., Dufour, E. M., Chew, T. W., Sorg, E. & Muller, W. A. The murine CD99-related molecule CD99-like 2 (CD99L2) is an adhesion molecule involved in the inflammatory response. Cell. Commun. Adhes. 14, 227–237 (2007).
Seelige, R. et al. Endothelial-specific gene ablation of CD99L2 impairs leukocyte extravasation in vivo. J. Immunol. 190, 892–896 (2013).
Stefanidakis, M., Newton, G., Lee, W. Y., Parkos, C. A. & Luscinskas, F. W. Endothelial CD47 interaction with SIRPγ is required for human T-cell transendothelial migration under shear flow conditions in vitro. Blood 112, 1280–1289 (2008).
Azcutia, V. et al. Endothelial CD47 promotes vascular endothelial-cadherin tyrosine phosphorylation and participates in T cell recruitment at sites of inflammation in vivo. J. Immunol. 189, 2553–2562 (2012).
Sullivan, D. P., Seidman, M. A. & Muller, W. A. Poliovirus receptor (CD155) regulates a step in transendothelial migration between PECAM and CD99. Am. J. Pathol. 182, 1031–1042 (2013).
Bixel, M. G. et al. CD99 and CD99L2 act at the same site as, but independently of, PECAM-1 during leukocyte diapedesis. Blood 116, 1172–1184 (2010).
Watson, R. L. et al. Endothelial CD99 signals through soluble adenylyl cyclase and PKA to regulate leukocyte transendothelial migration. J. Exp. Med. 212, 1021–1041 (2015).
Sorokin, L. The impact of the extracellular matrix on inflammation. Nat. Rev. Immunol. 10, 712–723 (2010).
Gotsch, U. et al. VE-cadherin antibody accelerates neutrophil recruiment in vivo. J. Cell Sci. 110, 583–588 (1997).
Schulte, D. et al. Stabilizing the VE-cadherin-catenin complex blocks leukocyte extravasation and vascular permeability. EMBO J. 30, 4157–4170 (2011).
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).
Nawroth, R. et al. VE-PTP and VE-cadherin ectodomains interact to facilitate regulation of phosphorylation and cell contacts. EMBO J. 21, 4885–4895 (2002).
Nottebaum, A. F. et al. VE-PTP maintains the endothelial barrier via plakoglobin and becomes dissociated from VE-cadherin by leukocytes and by VEGF. J. Exp. Med. 205, 2929–2945 (2008).
Vockel, M. & Vestweber, D. How T cells trigger the dissociation of the endothelial receptor phosphatase VE-PTP from VE-cadherin. Blood 122, 2512–2522 (2013).
Broermann, A. et al. Dissociation of VE-PTP from VE-cadherin is required for leukocyte extravasation and for VEGF-induced vascular permeability in vivo. J. Exp. Med. 208, 2393–2401 (2011). This paper shows that preventing the dissociation of VE-PTP from VE-cadherin inhibits neutrophil extravasation and the induction of vascular permeability in vivo.
Allingham, M. J., van Buul, J. D. & Burridge, K. ICAM-1-mediated Src- and Pyk2-dependent vascular endothelial cadherin tyrosine phosphorylation is required for leukocyte transendothelial migration. J. Immunol. 179, 4053–4064 (2007).
Turowski, P. et al. Phosphorylation of vascular endothelial cadherin controls lymphocyte emigration. J. Cell Sci. 121, 29–37 (2008).
Wessel, F. et al. Leukocyte extravasation and vascular permeability are each controlled in vivo by different tyrosine residues of VE-cadherin. Nat. Immunol. 15, 223–230 (2014). This in vivo study shows that phosphorylation and dephosphorylation of two tyrosine residues of VE-cadherin selectively and exclusively regulate either vascular permeability induction or leukocyte diapedesis, respectively.
Laukoetter, M. G. et al. JAM-A regulates permeability and inflammation in the intestine in vivo. J. Exp. Med. 204, 3067–3076 (2007).
Muller, W. A. Mechanisms of leukocyte transendothelial migration. Annu. Rev. Pathol. 6, 323–344 (2011).
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). This paper proposes the existence of a novel PECAM1-containing intracellular multivesicular compartment in endothelial cells that facilitates leukocyte diapedesis.
Mamdouh, Z., Mikhailov, A. & Muller, W. A. Transcellular migration of leukocytes is mediated by the endothelial lateral border recycling compartment. J. Exp. Med. 206, 2795–2808 (2009).
Schoefl, G. I. The migration of lymphocytes across the vascular endothelium in lymphoid tissue. A reexamination. J. Exp. Med. 136, 568–588 (1972).
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).
Millan, J. L. et al. Lymphocyte transcellular migration occurs through recruitment of endothelial ICAM-1 to caveola- and F-actin-rich domains. Nat. Cell Biol. 8, 113–123 (2006).
Nieminen, M. et al. Vimentin function in lymphocyte adhesion and transcellular migration. Nat. Cell Biol. 8, 156–162 (2006).
Yang, L. et al. ICAM-1 regulates neutrophil adhesion and transcellular migration of TNF-α-activated vascular endothelium under flow. Blood 106, 584–592 (2005).
Stan, R. V., Ghitescu, L., Jacobson, B. S. & Palade, G. E. Isolation, cloning, and localization of rat PV-1, a novel endothelial caveolar protein. J. Cell Biol. 145, 1189–1198 (1999).
Stan, R. V., Kubitza, M. & Palade, G. E. PV-1 is a component of the fenestral and stomatal diaphragms in fenestrated endothelia. Proc. Natl Acad. Sci. USA 96, 13203–13207 (1999).
Stan, R. V., Tkachenko, E. & Niesman, I. R. PV1 is a key structural component for the formation of the stomatal and fenestral diaphragms. Mol. Biol. Cell 15, 3615–3630 (2004).
Hallmann, R., Mayer, D. N., Berg, E. L., Broermann, R. & Butcher, E. C. Novel mouse endothelial cell surface marker is suppressed during differentiation of the blood brain barrier. Dev. Dyn. 202, 325–332 (1995).
Keuschnigg, J. et al. The prototype endothelial marker PAL-E is a leukocyte trafficking molecule. Blood 114, 478–484 (2009).
Rantakari, P. et al. The endothelial protein PLVAP in lymphatics controls the entry of lymphocytes and antigens into lymph nodes. Nat. Immunol. 16, 386–396 (2015).
Salmi, M. & Jalkanen, S. Ectoenzymes in leukocyte migration and their therapeutic potential. Semin. Immunopathol. 36, 163–176 (2014).
Salmi, M. & Jalkanen, S. Cell-surface enzymes in control of leukocyte trafficking. Nat. Rev. Immunol. 5, 760–771 (2005).
Rossi, E., Lopez-Novoa, J. M. & Bernabeu, C. Endoglin involvement in integrin-mediated cell adhesion as a putative pathogenic mechanism in hereditary hemorrhagic telangiectasia type 1 (HHT1). Front. Genet. 5, 457 (2015).
Rossi, E. et al. Endothelial endoglin is involved in inflammation: role in leukocyte adhesion and transmigration. Blood 121, 403–415 (2013).
Pappu, R. et al. Promotion of lymphocyte egress into blood and lymph by distinct sources of sphingosine-1-phosphate. Science 316, 295–298 (2007).
Schwab, S. R. & Cyster, J. G. Finding a way out: lymphocyte egress from lymphoid organs. Nat. Immunol. 8, 1295–1301 (2007).
Mandala, S. et al. Alteration of lymphocyte trafficking by sphingosine-1-phosphate receptor agonists. Science 296, 346–349 (2002).
Matloubian, M. et al. Lymphocyte egress from thymus and peripheral lymphoid organs is dependent on S1P receptor 1. Nature 427, 355–360 (2004).
Willinger, T., Ferguson, S. M., Pereira, J. P., De Camilli, P. & Flavell, R. A. Dynamin 2-dependent endocytosis is required for sustained S1PR1 signaling. J. Exp. Med. 211, 685–700 (2014).
Kanda, H. et al. Autotaxin, an LPA-producing ecto-enzyme, promotes lymphocyte entry into secondary lymphoid organs. Nat. Immunol. 9, 415–423 (2008).
Nakasaki, T. et al. Involvement of the lysophosphatidic acid-generating enzyme autotaxin in lymphocyte-endothelial cell interactions. Am. J. Pathol. 173, 1566–1576 (2008).
Zhang, Y., Chen, Y. C., Krummel, M. F. & Rosen, S. D. Autotaxin through lysophosphatidic acid stimulates polarization, motility, and transendothelial migration of naive T cells. J. Immunol. 189, 3914–3924 (2012).
Bai, Z. et al. Constitutive lymphocyte transmigration across the basal lamina of high endothelial venules is regulated by the autotaxin/lysophosphatidic acid axis. J. Immunol. 190, 2036–2048 (2013).
Chimen, M. et al. Homeostatic regulation of T cell trafficking by a B cell-derived peptide is impaired in autoimmune and chronic inflammatory disease. Nat. Med. 21, 467–475 (2015).
Semple, J. W., Italiano, J. E. J. & Freedman, J. Platelets and the immune continuum. Nat. Rev. Immunol. 11, 264–274 (2011).
Gleissner, C. A., von Hundelshausen, P. & Ley, K. Platelet chemokines in vascular disease. Arterioscler. Thromb. Vasc. Biol. 28, 1920–1927 (2008).
Karshovska, E. et al. Hyperreactivity of junctional adhesion molecule A-deficient platelets accelerates atherosclerosis in hyperlipidemic mice. Circ. Res. 116, 587–599 (2015).
Sreeramkumar, V. et al. Neutrophils scan for activated platelets to initiate inflammation. Science 346, 1234–1238 (2014).
Herzog, B. H. et al. Podoplanin maintains high endothelial venule integrity by interacting with platelet CLEC-2. Nature 502, 105–109 (2013).
Goerge, T. et al. Inflammation induces hemorrhage in thrombocytopenia. Blood 111, 4958–4964 (2008).
Boulaftali, Y. et al. Platelet ITAM signaling is critical for vascular integrity in inflammation. J. Clin. Invest. 123, 908–916 (2013).
Hillgruber, C. et al. Blocking neutrophil diapedesis prevents hemorrhage during thrombocytopenia. J. Exp. Med. 212, 1255–1266 (2015).
Rowe, R. G. & Weiss, S. J. Breaching the basement membrane: who, when and how? Trends Cell Biol. 18, 560–574 (2008).
Manevich-Mendelson, E. et al. Loss of Kindlin-3 in LAD-III eliminates LFA-1 but not VLA-4 adhesiveness developed under shear flow conditions. Blood 114, 2344–2353 (2009).
Hyduk, S. J. et al. Talin-1 and kindlin-3 regulate α4β1 integrin-mediated adhesion stabilization, but not G protein-coupled receptor-induced affinity upregulation. J. Immunol. 187, 4360–4368 (2011).
Anderson, D. C. & Springer, T. A. Leukocyte adhesion deficiency:an inherited defect in Mac-1, LFA-1, and p150/95 glycoprotein. Ann. Rev. Med. 38, 175–192 (1987).
Etzioni, A. et al. Recurrent severe infections caused by a novel leukocyte adhesion deficiency. N. Engl. J. Med. 327, 1789–1792 (1992).
Luhn, K., Wild, M. K., Eckhardt, M., Gerardy-Schahn, R. & Vestweber, D. The gene defective in leukocyte adhesion deficiency II encodes a putative GDP-fucose transporter. Nat. Genet. 28, 69–72 (2001).
Lübke, T. et al. Complementation cloning identifies CDG-IIc (LADII), a new type of congenital disorders of glycosylation, as a GDP-fucose-transporter deficiency. Nature Genet. 28, 73–76 (2001).
Kuijpers, T. W. et al. Leukocyte adhesion deficiency type 1 (LAD-1)/variant. J. Clin. Invest. 100, 1725–1733 (1997).
Svensson, L. et al. Leukocyte adhesion deficiency-III is caused by mutations in KINDLIN3 affecting integrin activation. Nat. Med. 15, 306–312 (2009).
Moser, M. et al. Kindlin-3 is required for β2 integrin-mediated leukocyte adhesion to endothelial cells. Nat. Med. 15, 300–305 (2009).
Malinin, N. L. et al. A point mutation in Kindlin-3 ablates activation of three integrin subfamilies in humans. Nat. Med. 15, 313–318 (2009).
Armulik, A., Genové, G. & Betsholtz, C. Pericytes: developmental, physiological, and pathological perspectives, problems, and promises. Dev. Cell 21, 193–215 (2011).
Proebstl, D. et al. Pericytes support neutrophil subendothelial cell crawling and breaching of venular walls in vivo. J. Exp. Med. 209, 1219–1234 (2012).
Voisin, M. B. & Nourshargh, S. Neutrophil transmigration: emergence of an adhesive cascade within venular walls. J. Innate Immunol. 5, 336–347 (2013).
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).
Wu, C. et al. Endothelial basement membrane laminin α5 selectively inhibits T lymphocyte extravasation into the brain. Nat. Med. 15, 519–527 (2009).
Pober, J. S. & Tellides, G. Participation of blood vessel cells in human adaptive immune responses. Trends Immunol. 33, 49–57 (2012).
Stark, K. et al. Capillary and arteriolar pericytes attract innate leukocytes exiting through venules and 'instruct' them with pattern-recognition and motility programs. Nat. Immunol. 14, 41–51 (2013).
Abtin, A. et al. Perivascular macrophages mediate neutrophil recruitment during bacterial skin infection. Nat. Immunol. 15, 45–53 (2014).
Larochelle, C. et al. Melanoma cell adhesion molecule identifies encephalitogenic T lymphocytes and promotes their recruitment to the central nervous system. Brain 135, 2906–2924 (2012).
Duan, H. et al. Targeting endothelial CD146 attenuates neuroinflammation by limiting lymphocyte extravasation to the CNS. Sci. Rep. 3, 1687 (2013).
Schneider-Hohendorf, T. et al. VLA-4 blockade promotes differential routes into human CNS involving PSGL-1 rolling of T cells and MCAM-adhesion of TH17 cells. J. Exp. Med. 211, 1833–1846 (2014).
Jin, S. et al. Nepmucin/CLM-9, an Ig domain-containing sialomucin in vascular endothelial cells, promotes lymphocyte transendothelial migration in vitro. FEBS Lett. 582, 3018–3024 (2008).
The author thanks A. Wintgens for help with the figures and acknowledges the Max Planck Society, the Deutsche Forschungsgemeinschaft (SFB629, SFB 1009 and SFB/TR 128) and the Cells-in-Motion (CiM) Excellence Cluster Münster for funding his research on this topic.
The author declares no competing financial interests.
- Pathogen-associated molecular patterns
(PAMPs). Microbial products that stimulate cells of the innate immune system by binding to an array of pattern-recognition receptors.
- Damage-associated molecular patterns
(DAMPs). Molecules that are released by stressed and damaged cells and function as endogenous danger signals by promoting the innate immune response.
Perivascular cells that wrap around capillaries and venules throughout the organism.
- Tight and adherens junctions
Intermingled junctions that form a belt of closely associated plasma membranes at cell contacts that regulate paracellular flux and cell contact stability between endothelial cells. The major components of these junctions are claudins, occludin, junctional adhesion molecules, endothelial cell-selective adhesion molecule and vascular endothelial cadherin.
A type of junction that is found in epithelial and muscle cells, where intermediate filaments are linked to the plasma membrane. Although blood vessel endothelial cells do not contain classical desmosomes, they do express desmosomal cadherins.
- Reverse transmigration
Transmigration of leukocytes in an abluminal-to-luminal direction under conditions of ischaemia–reperfusion injury.
- Lateral border recycling compartment
(LBRC). An endothelial intracellular vesicle compartment that forms a membrane network just below the plasma membrane at regions of cell contact. Stimulation of PECAM1 has been suggested to trigger the recycling of this membrane compartment to the junctional surface, where the additional membrane surface may help to accommodate the diapedesing leukocyte.
- Blood–brain barrier
The highly selective and tight barrier of the vascular wall of blood vessels of the brain that separates the circulating blood from the central nervous system.
- Hereditary haemorrhagic telangiectasia
A multiorgan vascular dysplasia characterized by multiple arteriovenous malformations that lack an intervening capillary network.
About this article
Cite this article
Vestweber, D. How leukocytes cross the vascular endothelium. Nat Rev Immunol 15, 692–704 (2015). https://doi.org/10.1038/nri3908
Current Opinion in Physiology (2021)
The FASEB Journal (2021)
Neurobiology of resilience in depression: immune and vascular insights from human and animal studies
European Journal of Neuroscience (2021)