Leukocytes on the Move: Adhesion and Diapedesis of Agranulocytes

The migration of leukocytes from the vascular system to sites of pathogenic exposure is a key event in the process of inflammation. Generally, agranulocyte (lymphocytes and monocytes) adhesion and passage from the bloodstream to the lymphatic system occurs in the lymphoid endothelial venule. Cell adhesion molecules which are involved in this process belong to three families: the selectins, the integrins, and members of the immunoglobulin super gene family. The process of extravasation or movement of agranulocytes involves the following steps: 1) tethering 2) rolling and activation 3) firm adhesion to the endothelium 4)diapedesis 5) transendothelial migration. Extravasation of agranulocytes requires specific cell-cell contacts between agranulocytes and endothelial cells lining the blood vessel. An inflammatory response, induced by infection or injury, triggers the movement of agranulocytes into body tissue towards the foreign invader. Agranulocytes normally circulate in the blood unattached and in response to inflammatory signals such as TNFs, interleukins, complement components and histamine, they adhere to the surface of the endothelium and then crawl forward (diapedesis) passing between neighboring endothelial cells (transmigration) to reach the infected tissues. These inflammatory signals induce endothelial cells to exocytose P-selectin and E-selectin and enhance the release of chemokines through transcytosis. The selectins bind to their respective ligands, PSGL1 and ESL1, and mediate the initiation of cell contact between agranulocytes and endothelial cells. L-Selectins in agranulocytes are recognized by E-selectins, GlyCAM1, MAdCAM1 and CD34 that act as ligands. This selectin-mediated tethering of agranulocytes to the blood vessel wall leads to a rolling movement of the agranulocytes on the lymphoid endothelial cell surface.Rolling cells sense signals from the endothelium which stimulate them to adhere more firmly to the endothelial cell surface. Such signals are chiefly relayed by chemokines through CXCRs/CCRs. Chemokines like the SDF1 are presented and immobilized by Sdcs. These stimulatory effects also cause the activation of integrins, which bind to members of the immunoglobulin superfamily on the endothelial cell surface. The major integrins involved in this process are LFA1, Itgα5/Itgβ1/2, Itgα4/Itgβ7, VLA4 and VLA5. These integrins bind to members of the immunoglobulin superfamily such as ICAM1, ICAM2, VCAM1 and MAdCAM1 on lymphoid endothelial cells resulting in tight adherence of agranulocytes to the endothelium, which activates the ERM proteins. This process is further enhanced when secreted fibronectin forms tight complexes with VLA5 and VLA4. This interaction leads to the activation of AOC3/VAP1, an enzyme that in turn activates PNAds and strengthens the binding of L-selectin and P-selectin to their respective ligands. This mechanism also enables the binding of PECAM1 and CD99 and facilitates the attachment of junctional adhesion proteins like JAM1 and JAM2 with integrins on the agranulocyte cell surface. This cross-linking results in the docking of agranulocytes on the apical surface of endothelial cells and triggering of signals including activation of MMPs. Activated MMPs and ROS degrade the assembly of junctional proteins like VEC and CAMs, leading to the opening of inter-endothelial cell contacts, allowing agranulocytes to transmigrate between adjacent endothelial cells to reach the underlying tissue.