Neutrophil Recruitment under Shear Flow: It's All about Endothelial Cell Rings and Gaps

Abstract

Leukocyte recruitment to tissues and organs is an essential component of host defense. The molecular mechanisms controlling this process are complex and remain under active investigation. The combination of biochemical techniques and live cell imaging using in vivo and in vitro flow model approaches have shed light on several aspects of neutrophil transmigration through the vascular endothelial lining of blood vessels. Here we focus on the role of adhesion molecule signaling in endothelial cells and their downstream targets during the process of transendothelial migration at cell-cell borders (paracellular transmigration). An emerging model involves leukocyte β2 integrin engagement of endothelial cell ICAM-1, which triggers integrin-ICAM-1 clustering (rings) and stabilizes leukocyte adhesion at cell-cell junctions. This step recruits nonreceptor tyrosine kinases that phosphorylate key tyrosine residues in the cytoplasmic tail of VE-cadherin, which destabilizes its linkage to catenins and the actin cytoskeleton, triggering the transient opening of VE-cadherin homodimers to form a gap in the cell junction, through which the neutrophil transmigrates. Interestingly, the signaling events that lead to neutrophil transmigration occur independent of shear flow in vitro.

Prevention of Neutrophil Extravasation by α2-Adrenoceptor–Mediated Endothelial Stabilization

“…In the course of leukocyte transmigration, endothelial cell junctions are transiently disassembled (50). Engagement of endothelial ICAM-1 by neutrophils leads to phosphorylation of the cytoplasmic domain of VE-cadherin, an essential process for efficient neutrophil extravasation (51).…”

Endothelial paxillin and focal adhesion kinase (FAK) play a critical role in neutrophil transmigration

“…During transmigration endothelial cells undergo rapid changes in their structural organization [5,6]. For example, the junctional protein vascular endothelial cadherin (VE-cadherin) is phosphorylated and redistributes during neutrophil transmigration [7][8][9].…”

“…During inflammation, neutrophils leave the bloodstream and traffic into the tissue in a well-described series of steps [1,2]. The molecular interactions governing the initial stages of tethering, rolling and firm adhesion have been well studied [1,2], whereas a clear picture of the latter steps underlying the passage of the leukocytes through the blood vessel has been slower to emerge [3][4][5].During transmigration endothelial cells undergo rapid changes in their structural organization [5,6]. For example, the junctional protein vascular endothelial cadherin (VE-cadherin) is phosphorylated and redistributes during neutrophil transmigration [7][8][9].…”

Wall structures of myocardial precapillary arterioles and postcapillary venules reexamined and reconstructed in vitro for studies on barrier functions

“…4). While the arteriolar capillary limb subserves the exchange of low-molecular-weight solutes and gases between the intravascular and interstitial spaces, the endothelial exchange area of the postcapillary venular system is generally designed for the rapid recruitment of the large protein molecules and cellular components of the immune system from the blood into inflamed areas (1,25). Indeed, postcapillary venules have a particularly responsive endothelium [postcapillary venular endothelium (PVE)] that, shortly after contact with inflammatory mediators, alters its typical morphology (68) characteristically, finally closely resembling the "high venular endothelium" in the lymph nodes (58).…”