How leukocytes cross the vascular endothelium

Key Points

  • 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.

Abstract

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.

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Figure 1: The multistep cascade of leukocyte extravasation.
Figure 2: Adhesion receptors function sequentially during leukocyte diapedesis.
Figure 3: Signalling steps that initiate the opening of endothelial cell junctions and regulate leukocyte diapedesis.

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Acknowledgements

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.

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Correspondence to Dietmar Vestweber.

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PowerPoint slides

Glossary

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.

Pericytes

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.

Desmosomes

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.

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Vestweber, D. How leukocytes cross the vascular endothelium. Nat Rev Immunol 15, 692–704 (2015). https://doi.org/10.1038/nri3908

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