How leukocytes trigger opening and sealing of gaps in the endothelial barrier

Abstract

The entry of leukocytes into tissues requires well-coordinated interactions between the immune cells and endothelial cells which form the inner lining of blood vessels. The molecular basis for recognition, capture, and adhesion of leukocytes to the endothelial apical surface is well studied. This review will focus on recent advances in our understanding of events following the firm interaction of leukocytes with the inner surface of the blood vessel wall. We will discuss how leukocytes initiate the transmigration (diapedesis) process, trigger the opening of gaps in the endothelial barrier, and eventually move through this boundary.

Keywords: Leukocytes; diapedesis; endothelial barrier; transmigration.

Figure 1.. Opening and closing of endothelial junctions during diapedesis.

( A) Leukocytes interacting with several adhesion molecules on the endothelial cell surface trigger Ca ²⁺ signals inside endothelial cells, which are essential for leukocyte transmigration. It was reported that Ca ²⁺ signals triggered by the apical adhesion molecules were initiated by stores from the endoplasmic reticulum but that PECAM-1 Ca ²⁺ transients occurred rather local at transmigration sites through the TRPC6 channel. Ca ²⁺ signals trigger the activation of actomyosin-mediated pulling on endothelial junctions, influence the phosphorylation of components of the VE-cadherin-catenin complex, and trigger the recycling of the lateral border recycling compartment (LBRC) vesicle compartment. For a more detailed depiction of intracellular signaling steps, the reader is referred to recent reviews ^– . ( B) When leukocytes have already transmigrated more than halfway through the site of diapedesis, RhoA-mediated signaling triggered by the RHO guanine nucleotide exchange factors (GEFs) Ect2 and LARG stimulates ROCK2b, which activates actomyosin-based forces that support pore confinement, which leads to closure of the diapedesis pore . Abbreviations: ICAM1, intercellular adhesion molecule 1; LFA-1, lymphocyte function-associated antigen 1; PECAM-1, platelet and endothelial cell adhesion molecule 1; PSGL-1, P-selectin glycoprotein ligand-1; TRPC6, transient receptor potential canonical-6; VCAM1, vascular cell adhesion molecule 1; VE-cadherin, vascular endothelial cadherin; VE-PTP, vascular endothelial protein tyrosine phosphatase; VLA-4, very late antigen-4.