The process by which cells leave the bloodstream and cross the endothelium to enter into various tissues is called extravasation. Although the particular molecules involved may differ in different situations, the fundamental process is the same. Extravasation can be divided into three stages – rolling, activation and firm attachment, and trans-endothelial migration. Once cells have left the bloodstream they must be guided to the right location within the tissue. The entrance of neutrophils into a site of inflammation is the best understood example and will be described to illustrate the basic steps involved in these processes.
1. Rolling. Neutrophils, like other leukocytes, normally travel in the centre of the blood flow away from the endothelium. At a site of inflammation asodilation occurs, slowing down and disturbing the blood flow so that the neutrophils can ‘bump’ along the endothelium, a process known as rolling. Due to the action of inflammatory mediators, especially TNFα, the endothelial cells are activated to express P-selectin and E-selectin on their surface. These selectins can bind to sialyl-Lewisx on the surface of the neutrophil, slowing down the neutrophil so that it rolls along the endothelium.
2. Activation and firm attachment. The binding of the selectins to the sialyl-Lewisx is not strong enough for the neutrophil to adhere strongly to the endothelium. Strong attachment requires the binding of the integrin LFA-1 on the neutrophil to ICAM-1 on the endothelium. Before it can bind to ICAM-1, the LFA-1 must change conformation. One of the factors produced in an inflammatory response is interleukin- 8 (IL-8), which is a chemokine. Chemokines are a group of cytokines with chemotactic and other functions. Some of the IL-8 produced is held in the extracellular matrix on the endothelial cell surface and can bind to IL-8 receptors on the neutrophil surface. The binding of IL-8 to the neutrophil activates the neutrophil and LFA-1 changes conformation and binds firmly to ICAM-1 on the endothelium.
3. Transendothelial migration. Once the neutrophil is firmly attached to the endothelium it squeezes between the endothelial cells, making contact with the basement membrane underneath. This process is poorly understood but involves additional adhesion molecules. Finally enzymes digest the basement membrane, allowing the leucocyte to pass through into the tissue space.
4. Movement in the site of inflammation. In the inflamed tissue there will be a gradient of IL-8, with maximum levels at the centre of infection. Neutrophils that have left the bloodstream and entered the tissue will travel along the IL-8 gradient, moving towards increasing concentration of the chemokine so that they will accumulate at the centre of infection.
The way in which other leukocytes cross endothelia, leave the bloodstream and migrate through tissues is essentially the same as for neutrophils, although the adhesion molecules and chemokines may be different for different cell types. Many adhesion molecules and chemokines exist to control adhesion, integrin activation and movement of different types of cells in various tissues. In sites of inflammation other factors such as complement components and prostaglandins can also act as chemoattractants.
