Ley Integration of inflammatory signals by rolling neutrophils

8 Summary: In inflammation, neutrophils roll along the endothelial wall of postcapillary venules and sample inflammatory signals. Neutrophil activation is required to generate b2 integrin bonds with the endothelium that are strong enough to withstand the flow forces and thus achieve arrest from the rolling state. Unlike naı̈ve T cells, neutrophils are not only activated by ligation of G-protein coupled receptors with chemokines and other chemoattractants but also receive signals from engagement of adhesion molecules including the selectins and b2 integrins. Rolling neutrophils integrate the sum total of inputs received while scanning the inflamed endothelium. In this process, the velocity of rolling neutrophils systematically decreases as a function of their contact time with the inflamed endothelium. If an activation threshold is reached, b2 integrins switch to the high-affinity conformation, redistribute on the cell surface, and trigger arrest and adhesion. Rolling cells that do not reach the activation threshold detach from the endothelium and are released back into the circulation. The role of chemokines, adhesion molecules, and other activating inputs involved in this response as well as signaling pathways are the subjects of ongoing investigations. This review provides a conceptual framework for neutrophil recruitment from the flowing blood.