Figure 1.

The leukocyte extravasation cascade is an elaborate process understood in part due to the use of well-controlled in vitro studies. Platforms incorporating vascular endothelial cells and physiological environmental conditions (e.g., shear stress) permit the highly controlled study of all steps of the leukocyte extravasation cascade: capture, rolling, arrest, intravascular crawling, and both paracellular and transcellular transendothelial migration. P and E selectin bind leukocytes to aid in the capture and rolling phases of extravasation. LFA-1/Mac-1: ICAM-1 and VLA-4: VCAM-1 form high affinity/avidity integrin/ligand interactions to halt leukocytes on the apical endothelial cell surface during arrest. Integrin activation is aided by chemokine signaling (neutrophil chemokine IL-8 and its receptors CXCR1/2 pictured here). In addition to leukocyte arrest and intravascular crawling, LFA-1/Mac-1: ICAM-1 interactions function to signal VE-cadherin junctional turnover and opening of the endothelial cell-cell junctions. Additionally, PECAM-1 and CD99 homophilic interactions between leukocytes and endothelial cells function to drive membrane mobilization from the lateral border recycling compartment (LBRC) to increase membrane surface area around the transmigrating leukocyte. The understanding of each of these components of leukocyte extravasation have been guided by the use of simple and modern in vitro systems. These same devices can, in turn, function as early stage drug discovery platforms for preventing devastating inflammatory diseases.