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Agranulocyte Adhesion and Diapedesis

Agranulocyte adhesion and diapedesis is the complex process by which lymphocytes and monocytes (types of white blood cells), exit the bloodstream and migrate through the blood vessel walls to reach tissues and organs where they can respond to infections, injuries, and other threats to the body's health.

Agranulocyte Adhesion and Diapedesis

Pathway Summary

The migration of leukocytes from the vascular system to sites of pathogenic exposure is a key event in the process of inflammation. Generally, agranulocyte (lymphocytes and monocytes) adhesion and passage from the bloodstream to the lymphatic system occurs in the lymphoid endothelial venule. Cell adhesion molecules which are involved in this process belong to three families: the selectins, the integrins, and members of the immunoglobulin super gene family. The process of extravasation or movement of agranulocytes involves the following steps: 1) tethering 2) rolling and activation 3) firm adhesion to the endothelium 4)diapedesis 5) transendothelial migration. Extravasation of agranulocytes requires specific cell-cell contacts between agranulocytes and endothelial cells lining the blood vessel. An inflammatory response, induced by infection or injury, triggers the movement of agranulocytes into body tissue towards the foreign invader. Agranulocytes normally circulate in the blood unattached and in response to inflammatory signals such as TNFs, interleukins, complement components and histamine, they adhere to the surface of the endothelium and then crawl forward (diapedesis) passing between neighboring endothelial cells (transmigration) to reach the infected tissues. These inflammatory signals induce endothelial cells to exocytose P-selectin and E-selectin and enhance the release of chemokines through transcytosis. The selectins bind to their respective ligands, PSGL1 and ESL1, and mediate the initiation of cell contact between agranulocytes and endothelial cells. L-Selectins in agranulocytes are recognized by E-selectins, GlyCAM1, MAdCAM1 and CD34 that act as ligands. This selectin-mediated tethering of agranulocytes to the blood vessel wall leads to a rolling movement of the agranulocytes on the lymphoid endothelial cell surface.Rolling cells sense signals from the endothelium which stimulate them to adhere more firmly to the endothelial cell surface. Such signals are chiefly relayed by chemokines through CXCRs/CCRs. Chemokines like the SDF1 are presented and immobilized by Sdcs. These stimulatory effects also cause the activation of integrins, which bind to members of the immunoglobulin superfamily on the endothelial cell surface. The major integrins involved in this process are LFA1, Itgα5/Itgβ1/2, Itgα4/Itgβ7, VLA4 and VLA5. These integrins bind to members of the immunoglobulin superfamily such as ICAM1, ICAM2, VCAM1 and MAdCAM1 on lymphoid endothelial cells resulting in tight adherence of agranulocytes to the endothelium, which activates the ERM proteins. This process is further enhanced when secreted fibronectin forms tight complexes with VLA5 and VLA4. This interaction leads to the activation of AOC3/VAP1, an enzyme that in turn activates PNAds and strengthens the binding of L-selectin and P-selectin to their respective ligands. This mechanism also enables the binding of PECAM1 and CD99 and facilitates the attachment of junctional adhesion proteins like JAM1 and JAM2 with integrins on the agranulocyte cell surface. This cross-linking results in the docking of agranulocytes on the apical surface of endothelial cells and triggering of signals including activation of MMPs. Activated MMPs and ROS degrade the assembly of junctional proteins like VEC and CAMs, leading to the opening of inter-endothelial cell contacts, allowing agranulocytes to transmigrate between adjacent endothelial cells to reach the underlying tissue.

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Frequently Asked Questions

What is the agranulocyte adhesion and diapedesis pathway?

The agranulocyte adhesion and diapedesis pathway is a complex immunological process that allows white blood cells, specifically monocytes and lymphocytes, to adhere to the endothelial cells lining blood vessels and then migrate through the vessel walls into surrounding tissues. This mechanism is a fundamental component of the immune response. The process is also known as monocyte trafficking or lymphocyte trafficking, depending on the specific type of agranulocyte involved.

What are agranulocytes, and how do they recognize sites of infection or inflammation?

Agranulocytes are a type of white blood cell that lacks distinctive granules in their cytoplasm. They play a crucial role in the immune system and can be divided into two main types: monocytes/macrophages and lymphocytes.

Monocytes/macrophages are large immune cells that can recognize sites of infection or inflammation through various mechanisms. They have receptors on their cell surface that can detect signals from pathogens, such as bacterial cell wall components or viral particles. Additionally, monocytes are attracted to sites of inflammation by chemokines, which are signaling molecules released by damaged tissues or immune cells already present at the site. Once they arrive, monocytes can further sense the local environment for signs of infection or tissue damage.

Lymphocytes, on the other hand, primarily recognize sites of infection or inflammation through specific antigens. These antigens can be presented by other immune cells, infected cells, or even pathogens themselves. Lymphocytes have receptors called T-cell receptors (TCRs) and B-cell receptors (BCRs) that can recognize these antigens. Additionally, chemokines and other immune signaling molecules can guide lymphocytes to the appropriate sites by creating chemical gradients that lead them to the source of the infection or inflammation.

What are the key adhesion molecules involved in agranulocyte adhesion and diapedesis?

Adhesion molecules are proteins that facilitate cell-to-cell or cell-to-matrix interactions. Several key adhesion molecules play crucial roles in the agranulocyte adhesion and diapedesis pathway and ensure that agranulocytes can effectively adhere to and migrate through the endothelium, so they can reach the infection or inflammation sites.

For monocytes and macrophages, integrins are prominent adhesion molecules involved in firm adhesion to the endothelial cells lining blood vessels. Integrin receptors on these immune cells, such as VLA-4 and LFA-1, interact with endothelial cell adhesion molecules like VCAM-1 and ICAM-1. This interaction helps monocytes and macrophages firmly adhere to the vessel wall, enabling them to initiate the process of diapedesis.

Lymphocytes, particularly T cells and B cells, utilize different sets of adhesion molecules. Selectins, such as L-selectin, E-selectin, and P-selectin, participate in the initial tethering and rolling steps, allowing lymphocytes to capture onto endothelial cells. Integrins like LFA-1 and VLA-4 are also crucial for lymphocyte firm adhesion. Additionally, chemokine receptors on lymphocytes, such as CXCR4 or CCR7, guide them to the appropriate sites based on chemotactic signals, facilitating their migration.

Why is agranulocyte adhesion essential for the immune response?

Agranulocyte adhesion is essential for the immune response because it allows immune cells like monocytes, macrophages, and lymphocytes to reach and infiltrate tissues where infections or inflammation are occurring. Without effective adhesion, these immune cells cannot leave the bloodstream and access the sites where they are needed most. Their presence within tissues is critical for pathogen clearance, tissue repair, and the regulation of immune reactions, ensuring a coordinated and effective immune response. 

What is diapedesis, and why is it important?

Diapedesis, also known as transmigration, is the intricate process by which immune cells migrate through the endothelial cell layer that lines blood vessels and subsequently enter the surrounding tissue. This process involves a series of precisely orchestrated steps, including the initial tethering and rolling of the immune cells along the endothelium, their firm adhesion to the endothelial cells, and their eventual passage through the endothelial barrier. Diapedesis is highly important in the immune response because it allows immune cells to reach the precise site of infection or inflammation, where they can effectively combat pathogens, release antimicrobial substances, and contribute to tissue repair. This ensures that the immune system is optimally positioned to protect the body against threats.

How is agranulocyte adhesion and diapedesis regulated?

Anti-inflammatory cytokines, like interleukin-10 (IL-10) and transforming growth factor-beta (TGF-β), play a crucial role in regulating adhesion and diapedesis. They dampen pro-inflammatory signaling pathways, inhibit the expression of adhesion molecules on endothelial cells, and reduce the availability of these molecules, thus preventing excessive adhesion and migration. Negative feedback mechanisms further contribute to the regulation of these processes, ensuring that once immune cells have reached their destination, further adhesion and migration are halted to prevent overaccumulation and potential tissue damage. 

What are the health effects of dysregulated adhesion and diapedesis?

Dysregulated agranulocyte adhesion and diapedesis can have significant health effects. When these processes become excessive or prolonged, they can lead to persistent immune cell accumulation and activation in tissues, contributing to chronic inflammation. This chronic inflammation is associated with a range of health conditions, including autoimmune diseases like rheumatoid arthritis and inflammatory bowel disease, where the immune system mistakenly targets the body's own tissues.

Conversely, insufficient agranulocyte adhesion and diapedesis can impair immune responses, leaving the body more vulnerable to infections and hindering its ability to address tissue damage promptly. This can be observed in immunodeficiency disorders where immune cells fail to effectively migrate to sites of infection or inflammation. Inadequate immune cell recruitment can also impact wound healing and tissue repair processes.

Leukocytes on the Move: Adhesion and Diapedesis of Agranulocytes

Agranulocyte adhesion and diapedesis is a crucial part of the immune response. The process is known by a variety of terms: agranulocyte extravasation and migration, leukocyte adhesion and transmigration, monocyte and lymphocyte recruitment, lymphocyte trafficking, and leukocyte infiltration. All of these describe the same fundamental mechanism, in which a subset of white blood cells adheres to blood vessel walls and migrates into surrounding tissues to carry out essential immune functions and help respond to infections, inflammation, and tissue damage.

Agranulocytes and the Immune Response

Leukocytes, commonly referred to as white blood cells, are essential immune system players responsible for detecting, confronting, and eliminating harmful pathogens from the body. These cells are categorized into two main groups: granulocytes and agranulocytes, which are named according to the presence or absence of distinct granules within their cytoplasm.

Agranulocytes (also called nongranulocytes or mononuclear leukocytes) include two types of cells: lymphocytes and monocytes. Lymphocytes consist of T cells, B cells, and natural killer cells, which are pivotal in the body's immune defense. These cells are responsible for specifically recognizing foreign antigens and tailoring the subsequent immune responses, including antibody production and the destruction of infected cells.

Monocytes are important because they serve as the immune system's first responders. They transform into macrophages and dendritic cells that can engulf pathogens, clear dead cells, and present antigens, thereby orchestrating the complex interactions of the body's immune defense.

Lymphocytes and monocytes circulate in the bloodstream and monitor for signs of infection or tissue damage. When they encounter such signals, the cells migrate to the affected tissues where they adhere to the blood vessel walls and travel through the endothelial barrier via the agranulocyte adhesion and diapedesis pathway. This exit from the bloodstream and into the tissue allows them to perform essential immune duties.

The Process of Agranulocyte Adhesion and Diapedesis

The agranulocyte adhesion and diapedesis pathway involves a complex set of interactions between various immune cells, chemokines, and cell adhesion molecules. These interactions help to guide agranulocytes through the walls of blood vessels to areas of inflammation or infection.

Tethering / Capture

During tethering, also known as capture, agranulocytes move towards the inner lining of blood vessels, which is composed of endothelial cells. Here, weak interactions occur between the adhesion molecules E-selectin and P-selectin on inflamed endothelial cells and L-selectin on the leukocytes. These interactions prevent the leukocytes from being washed away by the blood flow, creating an opportunity for more stable interactions to occur.

Rolling and Slow Rolling

Once tethered, the agranulocytes make controlled rolling movements along the endothelial surface. This rolling is facilitated by continued interactions between selectins on both cell types. These movements increase the likelihood of agranulocytes encountering inflammatory signals at a site of inflammation or infection and becoming activated.

Activation

While rolling, agranulocytes are exposed to various signals from the endothelial cells and surrounding microenvironment. These signals include interleukins, chemokines, and other mediators, which activate the agranulocytes and lead to the upregulation of adhesion molecules on the surface of agranulocytes. This results in more robust and effective rolling interactions, guiding agranulocytes to their intended destination within tissues.

Firm Adhesion / Arrest

Firm adhesion, or arrest, is a crucial step in the agranulocyte adhesion and diapedesis pathway. Here, agranulocytes firmly attach to the endothelial cells lining blood vessels, ensuring that they remain in place at the site of inflammation or infection.

Adhesion Strengthening and Spreading

Following arrest, adhesion between granulocytes and endothelial cells strengthens further. Integrins play a key role in this process, forming more stable bonds. Granulocytes also undergo a shape change, flattening and spreading against the endothelial cell surface. These changes in shape and enhanced adhesion prepare granulocytes for the subsequent steps.

Intravascular Crawling and Transmigration

Intravascular crawling is the process where agranulocytes move along the luminal surface of the endothelium, searching for suitable sites for transmigration. This step allows agranulocytes to explore the endothelial cell surface for regions where diapedesis can occur most effectively.

Paracellular and Transcellular Diapedesis / Transmigration

Agranulocytes use two main routes of transmigration: paracellular and transcellular. In paracellular transmigration, agranulocytes squeeze between adjacent endothelial cells through gaps known as tight junctions. In transcellular transmigration, agranulocytes migrate directly through individual endothelial cells, passing through the cell body. Both routes allow these important immune cells to cross the endothelial barrier and enter the surrounding tissue, contributing to the immune response.

Regulation of Agranulocyte Adhesion and Diapedesis

A complex interplay of factors finely tune the intensity and duration of the agranulocyte adhesion and diapedesis processes. Key regulatory factors include chemokines, anti-inflammatory cytokines, and adhesion molecules. Chemokines, which are small signaling proteins, function as chemoattractants, guiding agranulocytes to specific sites of infection or inflammation. They help modulate the intensity of adhesion and transmigration by binding to their receptors on agranulocytes, leading to integrin activation and enhanced adhesion to endothelial cells. This chemotactic response ensures that agranulocytes are recruited appropriately to sites where their immune functions are needed most.

Anti-inflammatory cytokines, such as interleukin-10 (IL-10) and transforming growth factor-beta (TGF-β), play a pivotal role in tempering the intensity of agranulocyte adhesion and diapedesis. These cytokines dampen pro-inflammatory signaling pathways and inhibit the expression of adhesion molecules on endothelial cells. By reducing the availability of adhesion molecules like ICAM-1 and VCAM-1, anti-inflammatory cytokines help prevent excessive agranulocyte adhesion and migration. This regulatory mechanism prevents collateral tissue damage and ensures a balanced immune response.

Furthermore, negative feedback mechanisms, including the downregulation of adhesion molecules and chemokine receptors, halt adhesion and migration once agranulocytes have effectively reached the infection or inflammation site. These intricate regulatory factors collectively orchestrate the precise control of agranulocyte adhesion and diapedesis, contributing to immune homeostasis and minimizing the risk of immunopathological conditions.

Consequences of Dysregulated Adhesion and Diapedesis in Agranulocytes

Dysregulated adhesion and diapedesis in monocytes/macrophages and lymphocytes can have significant consequences for the immune system and overall health. When these processes are not tightly controlled, several issues can arise. For example, persistent immune cell accumulation and activation in tissues results in chronic inflammation, which can contribute to various inflammatory disorders, including autoimmune diseases such as rheumatoid arthritis and inflammatory bowel diseases. In these conditions, immune cells may mistakenly target the body's own tissues, causing damage and exacerbating symptoms.

On the other hand, inadequate adhesion and diapedesis of agranulocytes can weaken immune responses. If immune cells fail to migrate efficiently to sites of infection or inflammation, the body's ability to combat pathogens is compromised. This can result in recurrent infections, prolonged illnesses, or an increased susceptibility to microbial invaders.

Further Reading

Chavakis E, Choi EY, Chavakis T. Novel aspects in the regulation of the leukocyte adhesion cascade. Thromb Haemost. 2009 Aug;102(2):191-7. doi: 10.1160/TH08-12-0844.

Filippi MD. Mechanism of Diapedesis: Importance of the Transcellular Route. Adv Immunol. 2016;129:25-53. doi: 10.1016/bs.ai.2015.09.001.

Filippi MD. Neutrophil transendothelial migration: updates and new perspectives. Blood. 2019 May 16;133(20):2149-2158. doi: 10.1182/blood-2018-12-844605.

Janeway CA Jr, Travers P, Walport M, et al. Immunobiology: The Immune System in Health and Disease. 5th edition. New York: Garland Science; 2001. The components of the immune system. Available from: https://www.ncbi.nlm.nih.gov/books/NBK27092/

Ley K, Laudanna C, Cybulsky MI, Nourshargh S. Getting to the site of inflammation: the leukocyte adhesion cascade updated. Nat Rev Immunol. 2007 Sep;7(9):678-89. doi: 10.1038/nri2156.

Mitroulis I, Alexaki VI, Kourtzelis I, Ziogas A, Hajishengallis G, Chavakis T. Leukocyte integrins: role in leukocyte recruitment and as therapeutic targets in inflammatory disease. Pharmacol Ther. 2015 Mar;147:123-135. doi: 10.1016/j.pharmthera.2014.11.008.

Muller WA. Getting leukocytes to the site of inflammation. Vet Pathol. 2013 Jan;50(1):7-22. doi: 10.1177/0300985812469883.

Nourshargh S, Alon R. Leukocyte migration into inflamed tissues. Immunity. 2014 Nov 20;41(5):694-707. doi: 10.1016/j.immuni.2014.10.008.

Petri B, Bixel MG. Molecular events during leukocyte diapedesis. FEBS J. 2006 Oct;273(19):4399-407. doi: 10.1111/j.1742-4658.2006.05439.x.