Granulocyte Adhesion and Diapedesis

The inflammatory reaction enables an organism to defend itself against infectious microbes. The migration of leukocytes or WBCs from the vascular system to sites of pathogenic exposure is a key event in the process of inflammation. Migration of leukocytes is initiated by the process of cell adhesion, followed by transmigration. These processes vary according to the nature of the blood vessels and type of leukocytes (granulocyte or agranulocyte) that are involved. Adhesion and diapedesis of granulocytes (neutrophils, basophils and eosinophils) have mostly been analyzed in the context of non-lymphoid endothelium. The polymorphonuclear neutrophils (PMNs) are the first line of host defense against infection by bacterial pathogens and are rapidly recruited to sites of bacterial invasion. Although eosinophils and basophils are the least abundant circulating leukocytes, an increasing body of evidence suggests that the latter play an active pathogenic role in allergic inflammation by releasing diverse pro-inflammatory mediators, including vasoactive amines, cysteinyl leukotrienes and cytokines.An inflammatory response induced by infection, injury or an allergen, triggers granulocytes to move into tissues towards the foreign invader, in a process called extravasation. In general, extravasation of leukocytes is a multi-step process that involves 1) tethering 2) rolling and activation 3) firm adhesion to the endothelium 4) diapedesis and finally 5) transendothelial migration. In response to inflammation, endothelial cells exocytose P-selectin and E-selectin and enhance release of chemokines through transcytosis. P-selectin and E-selectin bind to their respective ligands PSGL1 and ESL1, on granulocytes and mediate the initiation of cell contact between granulocytes and endothelial cells. In contrast to the rapidly flowing cells in the blood stream, rolling cells are able to sense signals from the endothelium which stimulates them to adhere more firmly to the endothelial cell surface. Such signaling molecules include chemokines which act through CXCRs /CCRs and G-protein. Often chemokines like SDF1 are presented and immobilized by Sdcs, cell surface proteoglycans, on the endothelium. These stimulatory effects cause activation of integrins, which in turn bind to members of the immunoglobulin superfamily on the endothelial cell surface. The major integrins involved in this process are LFA1 (a complex of Itg-αL and Itg-β2) and Mac1 (a complex of Itg-αM and Itg-β2) which bind to members of the immunoglobulin superfamily such as ICAM1, ICAM2 and VCAM1 on the non-lymphoid endothelial cell surfaces. This causes tight adherence of granulocytes to the endothelium.Cross-linking of integrins with ICAMs and VCAM1 activates the ERM (ezrin, radixin, moesin) proteins and recruits Thy1 to the cell surface. This interaction enables binding of PECAM1 and also facilitates attachment of junctional adhesion proteins like JAM2 and JAM3 with the granulocyte integrins. This cross-linking results in the docking of granulocytes to the apical surface of endothelial cell and triggers signals through generation of ROS and formation of stress fibers that further results in the activation of MMPs. Activated MMPs and ROS degrade the assembly of junctional proteins like VEC and other CAMs, leading to the opening of inter-endothelial cell contacts, allowing granulocytes to transmigrate and reach the underlying tissue.