Leukocyte adhesion cascade

From Wikipedia, the free encyclopedia

The Leukocyte adhesion cascade is a process through which leukocytes (white blood cells) leave blood vessels and enter injured tissue. This process results in inflammation. The five steps of the leukocyte adhesion cascade are:

capture (or transitory adhesion);
rolling;
slow rolling;
firm adhesion; and,
migration across the endothelium.

When cellular damage (trauma) occurs, the cells express (emit) P-selectin and secrete chemokines (for more information, please refer to Eukaryotic chemotaxis). Leukocytes naturally express the related molecule L-selectin. Selectin molecules have many surface receptors which are required for adhesive bonding. Leukocytes in the vicinity of damaged tissue are attracted by the presence of the chemokines. When the leukocyte gets close enough, the capture process initiates, and the leukocyte briefly adheres to the venular endothelium (inner cellular lining of veins). The leukocyte then rolls across the surface of the venular endothelium at a high speed (though more slowly than cells moving freely in the bloodstream). Rolling occurs when the selectin molecules bond to one another in the direction of the roll, but break bonds in the trailing direction. The speed of rolling may decrease (alternately, the leukocyte may break free), particularly in the case where E-selectin is expressed in the region. Eventually, a slow-rolling leukocyte will firmly adhere to the lining of the vein, as the selectin molecule receptors bond. The leukocyte will then travel through the cellular wall, following the chemokines trail to the source of the chemoattractants.

In an inflammatory response, leukocytes collectively are in every step of the cascade. Individually, they are in one step or another. It has been demonstrated that leukocyte recruitment is halted whenever any of the five steps is suppressed. It should be noted that suppressed expression of some selectin types (particularly L-selectin) will result in slower immune response. Normal immune response occurs in less than ten minutes. If L-selectin is not produced, the immune system response may be ten times slower, as P-selectin to P-selectin bonding occurs (leukocytes can also produce P-selectin). P-selectin to P-selectin bonds are equally strong, but occur less frequently because the receptor site density is lower than with the smaller E-selectin molecules; the resulting increase in initial rolling speed causes the slow rolling phase -- which ultimately allows firm adhesion and transmigration -- to take a longer period of time.

Firm binding to the endothelial surface occurs via integrin receptors present in the leukocyte cell membrane. Chemokines induce a conformational change in these integrin receptors (ie LFA)which allow them to bind to their ligand (ie ICAM). Transmigration of the leukocyte occurs as PECAM proteins, found on the leukocyte and endothelial surfaces, interact and effectively pull the cell through the endothelium. Chemotaxis then draws the leukocyte toward the site of injury.