Adhesion molecules in transendothelial emigration of monocytes

Under normal, noninflammatory conditions, a limited number of circulating monocytes adhere to and traverse the endothelial lining of the vessel wall. Under these conditions the efflux of monocytes from the circulation to the tissues ensures maintenance of the macrophage population in a given tissue compartment. During an inflammatory reaction, a variety of locally released inflammatory mediators, such as IL-la, TNFa, IFNy, chemoattractants (e.g. ana-phylatoxin C5a, leukotriene B4), formylmethionyl peptides (e.g. fMLP), or chemokines (e.g. IL-8 or monocyte chemotactic protein-1 (MCP-1)), can modulate the adhesion of monocytes to endothelial cells. The increased adhesion of monocytes to the vascular endothelium and subsequent migration to the inflamed tissue satisfies the demand for macrophages at that site.

Intravital microscopy studies revealed that extravasation of monocytes, and of leukocytes in general, is preceded by a coordinated sequence of adhesion events that enables these cells to withstand the hemodynamic forces generated by the flow of blood and to make firm contact with the vascular endothelial cells. Three separate consecutive events can be distinguished: monocytes first attach to the vessel wall in a rolling interaction, next the cells are arrested and stick firmly to the surface of endothelial cells and thereafter transendothelial migration by diapedesis occurs.

Rolling of monocytes along the endothelial lining of small venules is observed exclusively at inflammatory sites or sites of vascular injury and in vitro under conditions of flow. Rolling involves short-lived attachment of monocytes via L-seslectin to ligands such as P-selectin (CD62P), E-selectin (CD62E), or sialomucins (e.g. CD34, GlyCAM-1) on activated endothelial cells which is followed by detachment from the endothelium. Consequently the flow of monocytes in the main vasculature slows down. During rolling of the monocytes they become activated and enter the next phase of adhesion in which monocytes are arrested at a particular site of the vascular endothelium and migrate over the luminal surface of the endothelial cells.

The firm adhesion of monocytes to endothelium relies primarily on the activation of fj2-integrin molecules, resulting in an increase in affinity for their endothelial ligands (e.g. ICAM-1 ). However, also the (3|-integrin VLA-4 and CD14 mediate firm adhesion of monocytes to activated endothelium. Activation of p2-integrins may be triggered by the chcmokine MCP-1, which is produced by endothelial cells or elicited by binding of monocytes to the endothelial cell surface.

Monocytes finally cross the vessel wall by squeezing between tightly apposed endothelial cells in an ameboid fashion, called diapedesis, a process in which (32-integrin molecules are involved. This is concluded from the lack of neutrophil and monocyte diapedesis observed in patients with the leukocyte adhesion deficiency (LAD) syndrome, who are genetically deficient in the functional expression of leukocyte (3,-integrin molecules. However besides (32-integrins, hemophilic interaction of PECAM-1 on monocytes with PECAM-1 on the endothelial cells is also involved in transendothelial migration of monocytes.

Following diapedesis, monocytes attach to and subsequently traverse the subendothelial matrix, or basement membrane, consisting of fibronectin, lami-nin, collagen and sulfated proteoglycans, and enter the extravascular tissues.

See also: Diapedesis; Macrophage activation; Microbicidal mechanisms, oxygen-dependent; Microbicidal mechanisms, oxygen-independent; Mononuclear phagocyte system; Opsonization; Phagocytosis.

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