[Frontiers in Bioscience 14, 2522-2545, January 1, 2009]

Endothelial signaling in paracellular and transcellular leukocyte transmigration


Erika S. Wittchen

Department of Cell and Developmental Biology and Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599-7295, USA

TABLE OF CONTENTS

1. Abstract
2. Introduction
3. Molecular Players
3.1. Tight junction proteins
3.2. Adherens junction proteins
3.3. PECAM and CD99
3.4. EC-leukocyte adhesion molecules
3.4.1. ICAM-1
3.4.2. VCAM-1
3.5. GTPases and the cytoskeleton
3.5.1. Cytoskeleton
3.5.2. Rho family GTPases
3.5.3. Rap1 GTPase
4. Signaling events during TEM
4.1. ICAM-1
4.1.1. Rho GTPase signaling
4.1.2. Calcium signaling
4.1.3. Phosphorylation
4.1.4. VE-cadherin
4.1.5. Reactive oxygen species
4.2. VCAM-1
4.2.1. Rac activation and reactive oxygen species generation
4.2.2. Phosphorylation
5. EC apical cup structures
5.1. Mechanisms of assembly
6. Transcellular TEM
6.1. EC membrane structures in relation to transcellular TEM
6.2. Factors regulating transcellular TEM
6.3. Integrating EC membrane fusion events with leukocyte invasive podosomes
7. Summary and perspective
8. Acknowledgements
9. References

ABSTRACT

As the primary physical barrier between blood and tissue compartments within the body, blood vessel endothelial cells and integrity of the cell junctions connecting them must be carefully regulated to support leukocyte transendothelial migration only when necessary. Leukocytes utilize two independent routes across the endothelium: the paracellular route involves migration in-between adjacent endothelial cells and requires the transient disassembly of endothelial cell junctions, while the transcellular route occurs directly through an individual endothelial cell, likely requiring the formation of a channel or pore. In this review, I will first summarize the signaling events that are transduced by leukocyte engagement of endothelial cell-surface receptors like ICAM-1 and VCAM-1. Some of these signals include activation of GTPases, production of reactive oxygen species, and phosphorylation of target proteins. These signaling pathways converge to cause junctional disruption, cytoskeletal remodeling, and/or the membrane fusion events that are associated with leukocyte transendothelial migration. The review will conclude with a detailed discussion of the newly characterized transmigratory cup structure, and the recent advances made towards understanding the mechanisms of transcellular transendothelial migration.