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

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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/

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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.