Agranulocyte Adhesion and Diapedesis
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Agranulocyte Adhesion and Diapedesis

Homeostatic trafficking and coordinated infiltration into and within sites of inflammation and infection rely on signaling in response to extracellular cues that in turn controls a variety of intracellular protein networks regulating leukocyte motility, migration, chemotaxis, positioning, and cell-cell interaction. Leukocytes migrate in an amoeboid fashion by rapid cycles of actin polymerization and actomyosin contraction, and their migration in tissues is generally referred to as low adhesive and nonproteolytic (Ref.1). The migration of leukocytes or WBCs (White Blood Cells) from the vascular system to sites of pathogenic exposure is a key event in the process of inflammation. Generally, agranulocyte (which includes Lymphocytes and Monocytes) adhesion and passage from the bloodstream to the lymphatic system occurs in the high endothelial venules of the lymphnodes, also known as the lymphoid endothelial venule. Adhesion and Diapedesis of agranulocytes have mostly been analyzed in context to lymphocyte migration from lymphoid endothelial venules (Ref.2). The mechanism of transmigration varies according to the nature of the blood vessels and type of leukocytes. E-Selectin and enhance release of Chemokines are particularly well suited to mediate these signals. Firstly, they exist as a large multigene family and the use of distinct chemokines at specific anatomic sites contributes to specificity of leukocyte recruitment. Secondly, they act via GPCRs (G-Protein-Coupled Receptors) which are known to mediate rapid cellular responses. And thirdly, their association with proteoglycans allows efficient presentation at the luminal surface of the endothelium (Ref.3).

The inflammatory reaction enables the organism to defend itself against infectious microbes. The cell adhesion molecules which are involved in this process belong to three gene families that are: the Selectins, the Integrins, and members of the Immunoglobulin super gene family.The Extravasation of agranulocytes involves Tethering, Rolling and Activation, Firm Adhesion to the endothelium, Diapedesis and finally, Transendothelial migration (also known as Transmigration), the least characterized step. 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 (coagulation) or an allergen, triggers agranulocytes to move into tissues towards the foreign invader. Agranulocytes normally circulate in the blood unattached and in response to inflammatory signals such as TNFs (Tumor Necrosis Factors), Interleukins , Complement Components, Histamine, etc.,they adhere to the surface of endothelium and then crawl forward (Diapedesis) and pass between neighboring endothelial cells (Transmigration) to reach the infected tissues (Ref.4). These inflammatory signals induce endothelial cells to exocytose P-Selectin and E-Selectin and enhance release of Chemokines through Transcytosis. These inflammatory signals are conveyed via GPCRs. At the initial stage, the Selectins mediate the initiation of the cell contact between agranulocytes and endothelial cells. The P-Selectin and E-Selectin bind to their respective ligands PSGL1 (P-Selectin Glycoprotein Ligand) and ESL1 (E-Selectin Ligand-1). In case of agranulocytes, L-Selectins are recognized by E-Selectins,GlyCAM1 (Glycosylation Dependent Cell Adhesion Molecule-1), MAdCAM1 (Mucosal Vascular Addressin Cell Adhesion Molecule-1) and CD34 (CD34 Antigen) that act as lignads. L-Selectin occurs only on leukocytes. The GlyCAM1 and CD34 along with PodxL (Podocalyxin-Like) and SGp200 (Sulfated Glycoprotein of 200 KD), forms protein complex known as PNAd (Peripheral Node Addressins), whereas mucosal or mesenteric Addressin is thought to be the MAdCAM1. The gene for SGp200 has not been cloned as yet. Besides these proteins on the agranulocyte cell surface like the CLA (Cutaneous Lymphocyte Antigen) also bind to the E-Selectins, similar to action of SLe (Sialyl Lewis) structures that occur in granulocyte surfaces. The CLA-positive cells do not express SLe structures. However this adhesion is weak and the agranulocyte rolls along the endothelial cells. This Selectin-mediated tethering of agranulocytes to the blood vessel wall in combination with the rapidly flowing bloodstream leads to a rolling movement of the agranulocytes on the lymphoid endothelial cell surface (Ref.5 and 6).

In contrast to the rapidly flowing cells in the blood stream, the rolling cells are able to sense signals from the endothelium which stimulates them to adhere more firmly to the endothelial cell surface. Such signals to the agranulocytes are chiefly relayed by Chemokines through CXCRs (Chemokine (C-X-C) Receptors)/CCRs (Chemokine-CC-Motif Receptors). Often the Chemokines like the SDF1 (Stromal Cell-Derived Factor-1) are presented and immobilized by Sdcs (Syndecans), cell surface proteoglycans, on the endothelium. These stimulatory effects cause 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 (Leukocyte Function-Associated Antigen-1) (a complex of Itg-AlphaL (Integrin-Alpha-L) and Itg-Beta2 (Integrin-Beta-2)); Itg-Alpha9 (Integrin-Alpha-9)/Itg-Beta1 (Integrin-Beta-1); Itg-Alpha4 (Integrin-Alpha-4)/Itg-Beta7 (Integrin-Beta-7; VLA4 (Very Late Antigen-4) (comprising of Itg-Alpha4 and Itg-Beta1); and VLA5 (Very Late Antigen-5) (consisting of Itg-Alpha5 and Itg-Beta1) (Ref.6 and 7). However, cell surfaces of granulocytes like the Neutrophils do not express VLA4. These Integrins bind to members of the Immunoglobulin superfamily such as ICAM1 (Intercellular Adhesion Molecule-1), ICAM2, VCAM1 (Vascular Cell Adhesion Molecule-1) and MAdCAM1 on the lymphoid endothelial cells. This causes tight adherence of agranulocytes to the endothelium. Adhesion via activated Integrins is a prerequisite for the active migration of leukocytes on the endothelial cell surface and finally through the layer of endothelial cells (Ref.8).

Cross-linking of Integrins with ICAMs, VCAM1 and MAdCAM1 activates the ERM (Ezrin, Radixin, Moesin) proteins. This process is further enhanced when the secreted Fn (Fibronectin) and VLA5 forms tight complexes with VCAM1 and VLA4. This interaction leads to the activation of AOC3 (Amine Oxidase Copper Containing-3)/VAP1 (Vascular Adhesion Protein-1) that in turn activates PNAds and strengthens the binding of L-Selectin and P-Selectin with their respective ligands.This mechanism also enables binding of PECAM1 (Platelet Endothelial Cell Adhesion Molecule-1) and CD99 (CD99 Antigen) and also facilitates attachment of junctional adhesion proteins like PAM1 (Platelet Adhesion Molecule-1), previously known as JAM1 (Junctional Adhesion Molecule-1) and JAM2 (Junctional Adhesion Molecule-2) with the Integrins on agranulocyte cell surface. These cross-linking results in the docking of agranulocytes to the apical surface of endothelial cell and trigger signals through generation of ROS (Reactive Oxygen Species) and formation of stress fibers (altering Actin and Myosin structures) that further results in the activation of MMPs (Matrix Metalloproteinases). Activated MMPs and ROS degrade the assembly of junctional proteins like VEC (Vascular Endothelial Cadherin) and other CAMs (Cellular Adhesion Molecules),leading to the opening of inter-endothelial cell contacts and allowing agranulocytes to transmigrate between adjacent endothelial cells to reach the underlying tissue (Ref.9, 10 and 11). The unique interactions between activated agranulocytes and lymphoid endothelial cells, despite their complexity, helps to demonstrate that the avidity modulation or “inside-out" signaling is triggered by a variety of mechanisms that range from the binding of peptide and chemoattractants to membrane receptors to the cross-linking of other surface molecules. AThe promise of new insights into the biology and pathology of the inflammatory and immune response, and the potential for new therapies for a wide variety of diseases assures that this will continue to be an exciting area of investigation (Ref.12).