Rho-GTPase signaling in leukocyte extravasation: an endothelial point of view

Abstract

Leukocyte transendothelial migration (TEM) is one of the crucial steps during inflammation. A better understanding of the key molecules that regulate leukocyte extravasation aids to the development of novel therapeutics for treatment of inflammation-based diseases, such as atherosclerosis and rheumatoid arthritis. The adhesion molecules ICAM-1 and VCAM-1 are known as central mediators of TEM. Clustering of these molecules by their leukocytic integrins initiates the activation of several signaling pathways within the endothelium, including a rise in intracellular Ca (2+), activation of several kinase cascades, and the activation of Rho-GTPases. Activation of Rho-GTPases has been shown to control adhesion molecule clustering and the formation of apical membrane protrusions that embrace adherent leukocytes during TEM. Here, we discuss the potential regulatory mechanisms of leukocyte extravasation from an endothelial point of view, with specific focus on the role of the Rho-GTPases.

Keywords: GTPase; Rho-GEF; diapedesis; extravasation; signaling; transmigration.

Figure 1. The multistep process of leukocyte transendothelial migration, divided in five consecutive steps. Step 1 represents the rolling and tethering phase; step 2 shows the initial adhesion of the leukocytes to the endothelium. Step 3 is the firm adhesion and crawling part. In step 4, the cup-like structures are formed, resulting in step 5; actual transmigration, either para- or transcellular.

Figure 2. The cup-like structure. Signaling routes that are initiated by clustering of ICAM-1 and result in the remodeling of the actin cytoskeleton and the formation of cup-like structures. Signaling includes the activation of the small GTPases Rac1and RhoG downstream from ICAM-1 clustering and involvement of at least two GEFs, Trio and SGEF. Additionally, Rac1 activation may result in a positive feedback loop, increasing the clustering of ICAM-1.

Figure 3. Leukocyte adhesion-induced endothelial tension. Leukocyte adhesion results in the induction of actin-myosin contractility, as depicted in the figure, through the Rho-ROCK pathway or calcium signaling, resulting in MLC phosphorylation. This may finally result in the opening of cell–cell junctions, and thus, be involved in facilitating leukocyte TEM.