Granulocyte Adhesion and Diapedesis

Granulocyte adhesion and diapedesis – also referred to as granulocyte extravasation, granulocyte migration, leukocyte adhesion and transmigration, neutrophil recruitment, leukocyte trafficking, and leukocyte infiltration – represents a crucial process in the immune response. These various terms are often used interchangeably to describe the same fundamental mechanism in which a particular subset of white blood cells adhere to blood vessel walls and then migrate through the vessel walls into surrounding tissues to combat infections, assist in wound healing, or regulate immune reactions.

The Importance of Granulocyte Migration

White blood cells (also known as leukocytes) are an important part of the immune system, as they are responsible for detecting, attacking and removing pathogens from the body. There are two broad categories of white blood cells: granulocytes and agranulocytes, named according to the presence or absence of distinctive granules in their cytoplasm.

There are three types of granulocytes typically found circulating in the bloodstream: neutrophils, eosinophils, and basophils. Neutrophils are the most abundant type of white blood cell and are often the first responders to bacterial infections. They are highly effective at phagocytosis, which is the process of engulfing and digesting invading pathogens. Eosinophils are primarily involved in combating parasitic infections and regulating allergic responses, while basophils play a role in allergic reactions and immune responses to parasites.

Granulocytes are essential to the immune system because they are part of the body's first line of defense against invading pathogens. The ability of neutrophils, eosinophils, and basophils to migrate from the bloodstream to the site of infection or inflammation is crucial for a rapid and effective immune response. The granulocyte adhesion and diapedesis signaling pathway is the process through which these cells adhere to blood vessel walls and then migrate through the vessel walls into surrounding tissues. This pathway allows a precisely targeted response and the delivery of immune cells to the locations where they can combat infections, assist in wound healing, or regulate immune reactions.

Wound Healing

Neutrophils are vital for wound healing. When tissue is injured, neutrophils are among the first responders to migrate to the site of the wound. They help clear away debris and potential pathogens, facilitating the initial stages of tissue repair.

Bacterial Infections

Neutrophils are also highly effective against bacterial infections. When the body detects the presence of bacteria, neutrophils are recruited to the infected area. They can engulf and destroy bacteria through a process called phagocytosis, helping to eliminate the infection.

Parasitic Infections

Eosinophils are specialized in combating parasitic infections. When the body encounters parasitic invaders, eosinophils are mobilized to the site of infection. They release toxic substances that are effective against parasites, helping to limit their spread.

Allergic Responses

Basophils and eosinophils are involved in allergic reactions. When allergens enter the body, basophils release histamines and other inflammatory substances that contribute to allergy symptoms. Eosinophils, on the other hand, help regulate and control allergic responses, preventing them from becoming excessive.

The Granulocyte Adhesion and Diapedesis Process

Granulocyte adhesion involves a multi-step sequence of tightly regulated interactions between cell adhesion molecules, chemokines, and immune cells that guide the granulocytes through the blood vessel walls to sites of infection or inflammation.

Tethering / Capture

During tethering, which is also known as capture, granulocytes that are circulating in the bloodstream approach the inner lining of the blood vessel, which is composed of endothelial cells. Weak interactions between the adhesion molecules E-selectin and P-selectin on inflamed endothelial cells and L-selectin on the leukocytes prevents the leukocytes from being swept away by the blood flow and provides an opportunity for more stable interactions to take place.

Rolling and Slow Rolling

After tethering, the granulocytes make controlled rolling movements along the endothelial surface. This rolling is facilitated by continued interactions between selectins on both cell types. The movement of the granulocytes along the vessel wall increases their likelihood of encountering inflammatory signals at a site of infection or inflammation and becoming activated.

Activation

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

Firm Adhesion / Arrest

Firm adhesion (or arrest) is a critical step in the granulocyte adhesion and diapedesis pathway where granulocytes firmly attach to the endothelial cells lining blood vessels. This robust adhesion is mediated by integrins and ensures that granulocytes remain in place at the site of infection or inflammation.

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

Intravascular crawling, also known as lateral migration, is a process where granulocytes move along the luminal surface of the endothelium in search of suitable sites for transmigration. This step allows granulocytes to explore the endothelial cell surface for regions where diapedesis can occur most effectively.

Paracellular and Transcellular Diapedesis / Transmigration

Granulocytes can undergo two main routes of transmigration—paracellular and transcellular. In paracellular transmigration, granulocytes squeeze between adjacent endothelial cells through small gaps known as tight junctions. In transcellular transmigration, granulocytes migrate directly through individual endothelial cells, passing through the cell body. Both routes allow granulocytes to cross the endothelial barrier and enter the surrounding tissue.

Regulation of Granulocyte Adhesion and Diapedesis

The regulation of granulocyte adhesion and diapedesis is finely orchestrated by various regulatory factors, including anti-inflammatory cytokines. These cytokines, such as interleukin-10 (IL-10) and transforming growth factor-beta (TGF-β), play a crucial role in controlling the intensity and duration of adhesion and diapedesis. They exert their effects by dampening pro-inflammatory signaling pathways and inhibiting the expression of adhesion molecules on endothelial cells. By reducing the availability of adhesion molecules like selectins and ICAMs, anti-inflammatory cytokines help prevent excessive granulocyte adhesion and migration, thereby limiting tissue damage and inflammation. This regulation ensures a balanced immune response, where granulocytes are recruited appropriately without causing collateral harm.

Negative feedback mechanisms are integral to the precise regulation of granulocyte adhesion and diapedesis. These mechanisms act as a safeguard against excessive inflammation and immune cell activation. One crucial aspect of negative feedback is the downregulation of adhesion molecules and chemokine receptors.

When immune cells detect that they have reached the site of infection or inflammation, signaling pathways are activated to halt further adhesion and migration. This includes internalization and degradation of adhesion molecules and receptors. For instance, chemokine receptor internalization can occur, reducing the responsiveness of granulocytes to chemoattractants.

In addition, anti-inflammatory cytokines can also participate in downregulating the expression of adhesion molecules and chemokine receptors. These mechanisms collectively ensure that once the immune cells have effectively reached the infection or inflammation site, they do not continue to accumulate excessively, reducing the risk of tissue damage and chronic inflammation.

Dysregulation and the Clinical Implications

Dysregulation of granulocyte adhesion and diapedesis can lead to various pathological conditions. Excessive adhesion and migration may result in chronic inflammation, contributing to autoimmune diseases such as rheumatoid arthritis and systemic lupus erythematosus. In these conditions, the immune system mistakenly targets the body's own tissues due to heightened immune cell activity.

Conversely, insufficient adhesion and migration can compromise immune responses, leaving the body more susceptible to infections and impairing its ability to address tissue damage promptly, as seen in conditions like immunodeficiency disorders. Overall, balanced regulation of these processes is essential for maintaining immune homeostasis and preventing immunopathological conditions.

Therapeutic Potential

Researchers are actively exploring therapeutic strategies that target granulocyte adhesion and diapedesis for various medical conditions. In autoimmune diseases like rheumatoid arthritis or multiple sclerosis, therapies aim to inhibit specific adhesion molecules or chemokine receptors involved in immune cell infiltration into healthy tissues. This approach can help mitigate autoimmune responses and reduce tissue damage.

In the context of chronic inflammatory conditions such as atherosclerosis or inflammatory bowel diseases, there is interest in developing drugs that selectively regulate adhesion molecule expression or chemokine signaling. These medications could prevent excessive inflammation and tissue damage, thereby improving the overall management of chronic inflammatory disorders.

Additionally, in the field of cancer immunotherapy, researchers are investigating ways to enhance immune cell recruitment to tumors using granulocyte adhesion and diapedesis pathways. By improving the body's ability to deliver immune cells to cancerous tissues, these strategies aim to enhance the recognition and eradication of cancer cells, potentially boosting the effectiveness of cancer treatments.

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.