What Are The Steps Involved In Leukocyte Extravasation?
Extravasation refers to the multi-step process by which cells migrate from the bloodstream into the tissue via the vascular endothelium. Leukocyte extravasation has been extensively studied and is fairly well understood at the molecular level. The basic steps of the process are capture or tethering, rolling, adhesion, locomotion, transmigration (diapedesis), traversing basal lamina, and migration through the extracellular membrane.
- Capture or Tethering:
The laminar blood flow carries circulating leukocytes passively through the bloodstream in the center of the channel. Local hemodynamic changes lead to a significantly decreased blood flow rate in postcapillary venules at inflammatory sites. As a result of this, leukocytes are more likely to interact with the endothelial cells lining the vessel. The presence of leukocyte adhesion molecules on the surface of endothelial cells induced by the inflammatory response increases the likelihood that these contacts will result in productive binding.
The body should have a complex set of controls in place before allowing leukocytes to enter tissue because the inflammatory response can cause such significant tissue damage. The series of adhesion events necessary for extravasation resemble a combination lock. It is essential for the right molecules to interact quickly and in the right order.
- Rolling:
Histamine and other acute inflammatory mediators promote the translocation of P-selectin from Weibel-Palade bodies to the luminal surface of endothelial cells. Selectin ligands on the leukocytes interact with P-selectin. Lewis and blood group family sialylated, fucosylated carbohydrate residues bound to proteins are known as selectin ligands. However, any glycoprotein with the proper residue is a potential ligand for selectins. (For instance, L-selectin on leukocytes interacts with CD34 expressed by endothelial cells when modified to bear selectin ligands).
Selectin-ligand binding interactions have extremely quick on-and-off rates, allowing for the initial capture of quickly moving leukocytes from the bloodstream and tentative binding to the endothelium as they move along in a process aptly known as rolling. A second inducible selectin, E-selectin, is expressed by the endothelium that has been stimulated by proinflammatory cytokines for several hours. E-selectin encourages the slow rolling of leukocytes because it partially activates the integrins on the leukocyte.
- Activation:
Rolling and slow rolling is used to promote the leukocyte interaction with the endothelial cell so that chemokines and other proinflammatory agents present on the surface of the endothelial cells can further activate the leukocyte. These chemokines bind to heparin sulfate glycosaminoglycans on the luminal surface produced by the endothelium or by interstitial inflammatory cells and then transported to the luminal side of the endothelium.
A subset of G protein-coupled receptors on leukocytes called chemokine receptors interacts with chemokines to transmit signals that activate leukocyte integrins. The heterodimeric adhesion receptor family known as integrins is dormant in an inactive conformation. A conformational change brought on by integrin activation makes it easier for their ligands to bind. This is referred to as inside-out integrin activation because the signals that activate the integrins come from the same cell's chemokine receptors.
- Adhesion:
Once activated, leukocyte integrins firmly attach to their ligands on endothelial cells, causing leukocytes to bind on the endothelial surface. Leukocyte rolling is prevented by antibodies that interfere with selectins or their ligands or by genetic deletion of the same. Antibodies that inhibit integrin function or genetic deletion of leukocyte integrins do not inhibit rolling but do prevent leukocytes from adhering to the endothelium.
- Locomotion:
Leukocytes that are adhering move to the edges of nearby endothelial cells to prepare for extravasation. During direct intravital microscopy observation, some leukocytes move upstream against blood flow. A particular subset of leukocyte integrins and endothelial cell adhesion molecules mediate intraluminal crawling or locomotion.
- Diapedesis:
The process by which a leukocyte squeezes in an ameboid fashion across the endothelial cells is known as TEM or diapedesis. This always occurs at endothelial cell borders. The inflammatory response may have reached its breaking point at TEM. Rolling, activation, adhesion, and locomotion of leukocytes are all reversible processes, and the majority of leukocytes adhere to the postcapillary venule at the site of inflammation and reenter circulation. The leukocyte does not return after committing to diapedesis, at least not in the same cell type.
- Traversing Basal Lamina:
The paradigms of leukocyte extravasation change during TEM, with processes like capturing, rolling, tight adhesion, and locomotion all involving interaction in two dimensions at the plane of leukocyte-endothelial cell interaction. The leukocyte interacts in three dimensions as it moves across the endothelial cell, subendothelial basement membrane, pericytes, and interstitial tissue during transmigration. Transmigration primarily requires homophilic adhesion, in which one molecule on the leukocyte interacts with the same molecule expressed by the endothelial cell. In contrast to the previous adhesive events, which involve heterophilic adhesion (one molecule on the leukocyte binding to a different molecule on the endothelial cell), transmigration is a process that depends on homophilic adhesion. The first molecule to be demonstrated to play a specific role in mediating transmigration in vitro and in vivo is a platelet or endothelial cell adhesion molecule 1 (PECAM-1, PECAM, CD31).
- Migration Through Extracellular Membrane:
The leukocyte must first cross the border of the endothelial cell and then the adjacent interstitial tissue to reach the site of inflammation. Areas of the basement membrane where collagen IV and laminin 10 are expressed at low levels are traversed by neutrophils and monocytes. Although this may be the easiest route, it may have the benefit of requiring less proteolysis to deliver these leukocytes to the site of injury.
Conclusion
A complex series of adhesion events between leukocytes and endothelium ensure that leukocytes only leave the bloodstream at the inflammatory site, which is crucial for getting leukocytes to the site of injury or infection. The inflammatory response has two disadvantages. The majority of pathologies are caused by inflammation that lasts too long, is self-directed, or occurs at the wrong time or place. Consequently, careful control of the inflammatory response is essential for our health. While there is an inadequate amount of data regarding tumor cells, the diapedesis between the tumor cells is fundamentally different. However, it appears that the function of leukocytes as body guardians is reflected in the careful manipulation of endothelial cells. On the other hand, tumor cells exhibit destructive behaviors.
