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Leukocyte Extravasation - A Walkthrough

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Leukocyte extravasation involves a series of adhesive steps, which involves the movement of leukocytes into the site of injury or inflammation.

Written byDr. Tamilini Ravindran

Medically reviewed byDr. Basuki Nath Bhagat

Published At August 9, 2023
Reviewed AtAugust 9, 2023

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.

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Frequently Asked Questions

Adhesion molecules facilitate leukocyte extravasation by mediating leukocyte attachment to the endothelial cells that line blood arteries. This interaction depends on leukocyte migration from the circulation into surrounding tissues during inflammation or immunological responses.

Extravasation involves various white blood cell types, such as neutrophils, monocytes, and lymphocytes. These cells attach themselves to the endothelial cells that line blood arteries, move through the vessel wall, and are essential players in inflammation and immunological responses at infection or tissue injury sites.

Inflammatory signals, such as cytokines, generated in reaction to infection or tissue injury tend to cause leukocyte extravasation. These signals alter the endothelial cells that line blood arteries, encouraging the development of adhesion molecules that let leukocytes from the circulation adhere to and migrate into the surrounding tissues.

Diseases linked to impaired leukocyte extravasation, such as leukocyte adhesion deficiency (LAD) syndromes, result from genetic mutations affecting adhesion molecules or signaling pathways involved in the extravasation process. These conditions lead to compromised immune responses and increased susceptibility to infections.

Leukocytes recognize the site of infection or inflammation by detecting chemical signals, such as cytokines and chemokines, released by damaged tissues or invading pathogens. These signals guide leukocytes toward the affected area by inducing changes in their movement and promoting their adherence to the endothelial cells lining blood vessels, facilitating their extravasation into the surrounding tissues.

Chemotaxis plays a crucial role in leukocyte extravasation by guiding leukocytes toward sites of infection or inflammation. Chemical signals released by damaged tissues or invading pathogens act as chemoattractants, directing leukocytes to migrate along a concentration gradient toward the source of the signals and facilitating their recruitment to the affected area.

Leukocyte extravasation can be regulated or modulated for therapeutic purposes. Strategies, such as targeting adhesion molecules or chemokine receptors, can be employed to modulate the process. By controlling leukocyte recruitment, these approaches have potential therapeutic applications in conditions characterized by excessive inflammation or immune dysfunction.

Certain receptors are involved in the process by which leukocytes adhere to endothelial cells. These comprise immunoglobulin superfamily members like ICAM-1 and VCAM-1, as well as selectins and integrins. These receptors facilitate leukocytes' initial adhesion to endothelial cells and their subsequent extravasation into tissues during inflammatory or immunological reactions.

Inflammation facilitates leukocyte extravasation by triggering the release of inflammatory mediators such as cytokines and chemokines. These signals promote changes in the endothelial cells lining blood vessels, leading to increased expression of adhesion molecules that facilitate the attachment and migration of leukocytes into the surrounding tissues.

White blood cells' capacity to move from the circulation into tissues during immunological reactions or inflammation is weakened if leukocyte extravasation is hindered. This might result in inadequate immunological responses, persistent inflammation, and heightened vulnerability to infections or other immune-related conditions.

Leukocyte extravasation may be affected by age-related changes. The effectiveness of extravasation and immunological responses may be affected by changes in leukocyte function or changes in the expression of adhesion molecules on endothelial cells in older adults.

Cytokines are crucial in leukocyte extravasation as they initiate and coordinate the inflammatory response. They promote changes in endothelial cells, such as increased expression of adhesion molecules, which facilitate the attachment and migration of leukocytes from the bloodstream into the surrounding tissues during inflammation or immune responses.

Leukocyte extravasation is investigated in research and clinical settings using various experimental approaches. These may include in vitro studies using cell culture models to examine the interactions between leukocytes and endothelial cells and in vivo experiments utilizing animal or human subjects to observe the process in real time. Additionally, advanced imaging techniques such as intravital microscopy allow for direct visualization of leukocyte extravasation in living tissues.

The timeframe for leukocyte extravasation varies depending on factors such as the extent of inflammation and the specific context of the immune response. In general, leukocyte extravasation can occur rapidly, with leukocytes migrating from the bloodstream into tissues in response to inflammatory signals within minutes to hours.

Leukocyte extravasation differs between tissues. The process can vary depending on factors such as the type of blood vessels present, the expression of adhesion molecules on endothelial cells, and specific chemokines that attract particular leukocytes. These variations contribute to the tissue-specific immune responses observed in different body parts.

Abnormal leukocyte extravasation can contribute to chronic inflammatory conditions. Dysregulated or excessive leukocyte recruitment and infiltration into tissues can lead to sustained inflammation, tissue damage, and the development or exacerbation of chronic inflammatory disorders such as rheumatoid arthritis, inflammatory bowel disease, or atherosclerosis.

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Dr. Basuki Nath Bhagat

Family Physician

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