Crossing the Vascular Wall: Common and Unique Mechanisms Exploited by Different Leukocyte Subsets during Extravasation

Abstract

Leukocyte extravasation is one of the essential and first steps during the initiation of inflammation. Therefore, a better understanding of the key molecules that regulate this process may help to develop novel therapeutics for treatment of inflammation-based diseases such as atherosclerosis or rheumatoid arthritis. The endothelial adhesion molecules ICAM-1 and VCAM-1 are known as the central mediators of leukocyte adhesion to and transmigration across the endothelium. Engagement of these molecules by their leukocyte integrin receptors initiates the activation of several signaling pathways within both leukocytes and endothelium. Several of such events have been described to occur during transendothelial migration of all leukocyte subsets, whereas other mechanisms are known only for a single leukocyte subset. Here, we summarize current knowledge on regulatory mechanisms of leukocyte extravasation from a leukocyte and endothelial point of view, respectively. Specifically, we will focus on highlighting common and unique mechanisms that specific leukocyte subsets exploit to succeed in crossing endothelial monolayers.

Figure 1

General scheme of the leukocyte extravasation cascade. The different steps of leukocyte interactions with endothelial cells during adhesion and transmigration are depicted. The known adhesion receptor interactions are listed for each step with the leukocyte receptor being named first. Unknown ligands are represented by question marks. During rolling, secondary rolling of leukocytes on already adherent leukocytes can occur that involve interactions of leukocyte L-selectin with leukocyte PSGL1 (not depicted). All receptors are connected to the actin cytoskeleton via actin-binding proteins to facilitate the extensive actin remodeling required for the morphological changes and movement of both cell types involved (not depicted). For details, see text.

Figure 2

Endothelial signaling pathways induced upon clustering of ICAM-1 and VCAM-1 leading to the formation of endothelial F-actin-rich apical cup structures and the dissociation of endothelial adherens junctions. Endothelial signals that are induced by specific leukocyte types are color-coded: neutrophils in green, monocytes in red, T cells in blue, and B cells in purple. In case signaling proteins are identified by studies using different leukocyte types, the background color of the protein name is adapted to the leukocyte type used. In case specific signaling is studied in the absence of leukocytes the color is black. Short stripes indicate glycosylation. Question mark indicates that GlyCAM-1, as a soluble protein, may reassociate to the endothelial membrane.