In immunology, leukocyte extravasation (also commonly known as leukocyte adhesion cascade or diapedesis – the passage of cells through the intact vessel wall) is the movement of leukocytes (white blood cells) out of the circulatory system (extravasation) and towards the site of tissue damage or infection. This process forms part of the innate immune response, involving the recruitment of non-specific leukocytes. Monocytes also use this process in the absence of infection or tissue damage during their development into macrophages.
Overview
Leukocyte extravasation occurs mainly in post-capillary venules, where haemodynamic shear forces are minimised. This process can be understood in several steps:
Chemoattraction Rolling adhesion Tight adhesion (Endothelial) Transmigration It has been demonstrated that leukocyte recruitment is halted whenever any of these steps is suppressed. White blood cells (leukocytes) perform most of their functions in tissues. Functions include phagocytosis of foreign particles, production of antibodies, secretion of inflammatory response triggers (histamine and heparin), and neutralization of histamine. In general, leukocytes are involved in the defense of an organism and protect it from disease by promoting or inhibiting inflammatory responses. Leukocytes use the blood as a transport medium to reach the tissues of the body. Here is a brief summary of each of the four steps currently thought to be involved in leukocyte extravasation:
Chemoattraction
Upon recognition of and activation by pathogens, resident macrophages in the affected tissue release cytokines such as IL-1, TNFα and chemokines. IL-1, TNFα and C5a cause the endothelial cells of blood vessels near the site of infection to express cellular adhesion molecules, including selectins. Circulating leukocytes are localised towards the site of injury or infection due to the presence of chemokines.
Rolling adhesion Like velcro, carbohydrate ligands on the circulating leukocytes bind to selectin molecules on the inner wall of the vessel, with marginal affinity. This causes the leukocytes to slow down and begin rolling along the inner surface of the vessel wall. During this rolling motion, transitory bonds are formed and broken between selectins and their ligands. For example, the carbohydrate ligand for P-selectin, P-selectin glycoprotein ligand-1 (PSGL-1), is expressed by different types of leukocytes (white blood cells). The binding of PSGL-1 on the leukocyte to P-selectin on the endothelial cell allows for the leukocyte to roll along the endothelial surface. This interaction can be tuned by the glycosylation pattern of PSGL-1, such that certain glycovariants of PSGL-1 will have unique affinities for different selectins, allowing in some cases for cells to migrate to specific sites within the body (e.g. the skin).
Tight adhesion At the same time, chemokines released by macrophages activate the rolling leukocytes and cause surface integrin molecules to switch from the default low-affinity state to a high-affinity state. This is assisted through juxtacrine activation of integrins by chemokines and soluble factors released by endothelial cells. In the activated state, integrins bind tightly to complementary receptors expressed on endothelial cells, with high affinity. This causes the immobilization of the leukocytes, which varies in vessels that contain different shear forces of the ongoing blood flow.
Transmigration The cytoskeletons of the leukocytes are reorganized in such a way that the leukocytes are spread out over the endothelial cells. In this form, leukocytes extend pseudopodia and pass through gaps between endothelial cells. This passage of cells through the intact vessel wall is called diapedesis. These gaps can form through interactions of the leukocytes with the endothelium, but also autonomously through endothelial mechanics. Transmigration of the leukocyte occurs as PECAM proteins, found on the leukocyte and endothelial cell surfaces, interact and effectively pull the cell through the endothelium. Once through the endothelium, the leukocyte must penetrate the basement membrane. The mechanism for penetration is disputed, but may involve proteolytic digestion of the membrane, mechanical force, or both. The entire process of blood vessel escape is known as diapedesis. Once in the interstitial fluid, leukocytes migrate along a chemotactic gradient towards the site of injury or infection.
Molecular biology
Introduction
The phases of the leukocyte extravasation depicted in the schema are: approach, capture, rolling, activation, binding, strengthening of the binding and spreading, intravascular creeping, paracellular migration or transcellular migration.
Selectins Selectins are expressed shortly after cytokine activation of endothelial cells by tissue macrophages. Activated endothelial cells initially express P-selectin molecules, but within two hours after activation E-selectin expression is favoured. Endothelial selectins bind carbohydrates on leukocyte transmembrane glycoproteins, including sialyl-LewisX.
P-selectins: P-selectin is expressed on activated endothelial cells and platelets. Synthesis of P-selectin can be induced by thrombin, leukotriene B4, complement fragment C5a, histamine, TNFα or LPS. These cytokines induce the externalisation of Weibel-Palade bodies in endothelial cells, presenting pre-formed P-selectins on the endothelial cell surface. P-selectins bind PSGL-1 as a ligand. E-selectins: E-selectin is expressed on activated endothelial cells. Synthesis of E-selectin follows shortly after P-selectin synthesis, induced by cytokines such as IL-1 and TNFα. E-selectins bind PSGL-1 and ESL-1. L-selectins: L-selectins are constitutively expressed on some leukocytes, and are known to bind GlyCAM-1, MadCAM-1 and CD34 as ligands. Suppressed expression of some selectins results in a slower immune response. If L-selectin is not produced, the immune response may be ten times slower, as P-selectins (which can also be produced by leukocytes) bind to each other. P-selectins can bind each other with high affinity, but occur less frequently because the receptor-site density is lower than with the smaller E-selectin molecules. This increases the initial leukocyte rolling speed, prolonging the slow rolling phase.
Integrins Integrins involved in cellular adhesion are primarily expressed on leukocytes. β2 integrins on rolling leukocytes bind endothelial cellular adhesion molecules, arresting cell movement.
… excerpt ends here. Continue reading the full article.
