A key stage in inflammation is the recruitment of circulating white blood cells or leukocytes to the endothelial cells lining the blood vessels inner wall, and subsequent migration of leukocytes into the surrounding tissue. Neutrophils are the most common circulating leukocytes, and are responsible for the bodys first response to invading bacteria. Circulating neutrophils must undergo a series of activation steps to respond to a local bacterial infection.
Neutrophils are recruited from circulation to the blood vessel endothelium
by a series of distinct steps as shown in the above graphic.
Neutrophils respond to inflammation through three classes of surface protein: selectins, integrins, and chemokines. To resist shear forces within the blood vessel, a neutrophil initially binds the blood vessel wall through selectins and undergoes a transient, rolling adhesion to the blood vessel. Integrins expressed by neutrophils change shape in response to activating signals such as chemokines, causing the neutrophil to decelerate from rolling to a stable arrest. Finally, the combination of chemokines and integrin engagement results in a second activation that causes the neutrophil to transform from a spherical circulating cell into an oblong migratory cell.
Our lab investigates how engagement of neutrophils by selectins and integrins contributes to activation of arrest and migration. We have found that neutrophil integrins expressed in a shape that binds strongly to endothelial ligands (high affinity) cooperate with chemokines to enhance neutrophil migration. Recently we have begun to use microfluidics and real time fluorescent imaging to measure the calcium concentration within neutrophils as they decelerate to arrest on cultured endothelial cells. Results suggest that calcium flux at the earliest stages of activation is a requirement for neutrophil arrest and migration on endothelium.