Rho GTPases and leucocyte-induced endothelial remodelling - PubMed (original) (raw)

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Rho GTPases and leucocyte-induced endothelial remodelling

Jaime Millán et al. Biochem J. 2005.

Abstract

Leucocytes in the bloodstream respond rapidly to inflammatory signals by crossing the blood vessel wall and entering the tissues. This process involves adhesion to, and subsequent transmigration across, the endothelium, mediated by a cascade of interactions between adhesion molecules and stimulation of intracellular signalling pathways in both leucocytes and endothelial cells. This leads to changes in endothelial cell morphology that assist leucocyte extravasation, including endothelial cell contraction, intercellular junction disruption, increased permeability, remodelling of the endothelial apical surface and alterations in vesicle trafficking. Rho GTPases play a central role in many of the endothelial responses to leucocyte interaction. In this review, we discuss recent findings on leucocyte-induced alterations to endothelial cells, and the roles of Rho GTPases in these responses.

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Figures

Figure 1

Figure 1. Possible remodelling of the endothelium caused by leucocyte interaction

Based on signalling induced by ligation (either by leucocytes or by specific antibodies) of endothelial receptors involved in each step of the cascade of transmigration, leucocytes may alter the endothelium in several ways. During the initial tethering and rolling, E-selectin may transiently signal to the actin cytoskeleton and redistribute caveolae. During firm adhesion, the turnover of focal adhesions may be altered and ICAM-1- and VCAM-1-mediated signalling may increase actomyosin contractility. VCAM-1 would also cause disruption of adherens junctions. During TEM, PECAM-1 could be translocated from an internal compartment to the plasma membrane. Simultaneously, a haptotactic gradient of chemokines may guide the leucocyte to the VVOs formed by caveolae. Each of these processes may guide the leucocyte towards either a paracellular or a transcellular route for TEM.

Figure 2

Figure 2. The roles of RhoA and Rac in leucocyte-induced signalling to the endothelium

(A) ICAM-1, and probably VCAM-1, ligation induces RhoA activation and triggers the formation of stress fibres and actomyosin contractility by increasing the phosphorylation of MLC. In addition, VCAM-1 clustering induces Rac1-mediated generation of ROS via NADPH oxidase, which disrupts adherens junctions. Phosphorylation of FAK, paxillin and Cas proteins induced by ICAM-1 cross-linking may contribute to alter the turnover of endothelial focal adhesions. (B) T-lymphoblasts or ICAM-1 ligation induce RhoA-mediated stress fibre formation. HUVECs were incubated with T-lymphoblasts or clustered with anti-ICAM-1 specific antibodies for 45 min, and ICAM-1 and F-actin were detected with an anti-ICAM-1 antibody or phalloidin respectively. Bar, 20 μm. (C) A 4-fold magnification of the squared area in (B) is shown. Transmigratory T-lymphoblast is surrounded by a microvillus-like docking structure. Despite being enriched in adhesion receptors involved in leucocyte firm adhesion, abrogation of these structures inhibits leucocyte TEM, but not adhesion [12]. ROCK may mediate the formation of these docking complexes [11]. Images in (B) and (C) were taken with a coolview 12-bit integrating cooled CCD camera (Photonic Science, Robertsbridge, East Sussex, U.K.) mounted over an Axiophot microscope (Carl Zeiss Ltd, Welwyn Garden City, Herts., U.K.).

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References

    1. Butcher E. C. Leukocyte–endothelial cell recognition: three (or more) steps to specificity and diversity. Cell. 1991;67:1033–1036. - PubMed
    1. Muller W. A. Leukocyte–endothelial-cell interactions in leukocyte transmigration and the inflammatory response. Trends Immunol. 2003;24:327–334. - PubMed
    1. Ostermann G., Weber K. S., Zernecke A., Schroder A., Weber C. JAM-1 is a ligand of the beta(2) integrin LFA-1 involved in transendothelial migration of leukocytes. Nat. Immunol. 2002;3:151–158. - PubMed
    1. Schenkel A. R., Mamdouh Z., Chen X., Liebman R. M., Muller W. A. CD99 plays a major role in the migration of monocytes through endothelial junctions. Nat. Immunol. 2002;3:143–150. - PubMed
    1. Vicente-Manzanares M., Sanchez-Madrid F. Role of the cytoskeleton during leukocyte responses. Nat. Rev. Immunol. 2004;4:110–122. - PubMed

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