Leukocyte extravasation
In general, leukocytes are involved in the defense of an organism and protect it from disease by promoting or inhibiting inflammatory responses.
Here is a brief summary of each of the four steps currently thought to be involved in leukocyte extravasation: Upon recognition of and activation by pathogens, resident macrophages in the affected tissue release cytokines such as IL-1, TNFα and chemokines.
IL-1, TNFα and C5a[1] cause the endothelial cells of blood vessels near the site of infection to express cellular adhesion molecules, including selectins.
[citation needed] Like velcro, carbohydrate ligands on the circulating leukocytes bind to selectin molecules on the inner wall of the vessel, with marginal affinity.
This interaction can be tuned by the glycosylation pattern of PSGL-1, such that certain glycovariants of PSGL-1 will have unique affinities for different selectins, allowing in some cases for cells to migrate to specific sites within the body (e.g. the skin).
In the activated state, integrins bind tightly to complementary receptors expressed on endothelial cells, with high affinity.
P-selectins can bind each other with high affinity, but occur less frequently because the receptor-site density is lower than with the smaller E-selectin molecules.
β2 integrins on rolling leukocytes bind endothelial cellular adhesion molecules, arresting cell movement.
Intracellular integrin domains associate with the leukocyte cytoskeleton, via mediation with cytosolic factors such as talin, α-actinin and vinculin.
This association causes a conformational shift in the integrin's tertiary structure, allowing ligand access to the binding site.
Extravasation is regulated by the background cytokine environment produced by the inflammatory response, and is independent of specific cellular antigens.
Cytokines released in the initial immune response induce vasodilation and lower the electrical charge along the vessel's surface.
Binding interactions between the white blood cells and the vessel walls were observed to become stronger under higher force.
L-selectin requires a particular minimum of shear to sustain leukocyte rolling on P-selectin glycoprotein ligand-1 (PSGL-1) and other vascular ligands.
[9][11] Schematic mechanisms of how increased shear force is proposed to cause stronger binding interactions between bacteria and target cells show that the catch bond acts very similar to a Chinese finger trap.
[12] Although flow chambers have been an important tool to study leukocyte rolling, there are several limitations when it comes to studying the physiological in vivo conditions, as they lack correspondence with in vivo geometry, including scale/aspect ratio (microvasculature vs large vessel models), flow conditions (e.g. converging vs diverging flows at bifurcations), and require large reagent volumes (~ ml) due to their large size (height > 250 μm and width > 1mm).
A new in vitro model, called SynVivo Synthetic microvascular network (SMN) was produced by the CFD Research Corporation (CFDRC) and developed using the polydimethylsiloxane (PDMS) based soft-lithography process.
In widespread diseases such as sepsis, leukocyte extravasation enters an uncontrolled stage, where white blood neutrophils begin destroying host tissues at unprecedented rates, claiming the lives of about 200,000 people in the United States alone.
This has high implications in various diseases, where disruptions in blood flow gravely impact immune system response by impeding or expediting the immobilization of the leukocytes.
