Subcellular events in the endothelium during chemokine-directed leukocyte extravasation.

(A) Noninflamed tissue. (B) Inflamed tissue. Release of chemokines from extravascular cells in the tissue occurs (→), and there is wrinkling of the endothelial cell surface. Chemokines are taken up at the abluminal surface of the endothelium and transcytosed in caveolae. This process involves binding to glycosaminoglycans (GAGs) and/or the Duffy receptor. At the luminal surface, chemokines are released and bound preferentially on the tips of projections. These mediators may also be produced and released directly by endothelial cells, in which case they are also bound at the luminal surface but not transcytosed (- - ->). (C) Chemokines bound at the luminal endothelial cell surface build up in concentration. They do this sufficiently to bind to and activate the signaling receptors on the leukocyte cell surface, leading to activation of integrins and firm attachment. (D) Leukocyte migration occurs either transcellularly through a pore in the endothelial cell or through the intercellular junction, following a chemokine gradient bound to GAGs and/or the Duffy receptor. The cell then enters the basement membrane and continues migration along a chemokine gradient that is soluble or immobilized to the extracellular matrix.