Endothelial cell activation leads to neutrophil transmigration as supported by the sequential roles of ICAM-2, JAM-A, and PECAM-1

Reactive Oxygen Species in Inflammation and Tissue Injury

“…Interestingly, the role of JAM-A, PECAM1, and ICAM-2 in neutrophil migration appears to be stimulus dependent. Neutrophil migration was suppressed in PECAM1, ICAM-2, or JAM-1 knockout mice on treatment of IL-1b and ischemia reperfusion injury; whereas TNF-a-induced neutrophil migration was unaffected in these knockout models (458). The mechanism behind stimulusdependent specificity of these junctional proteins is not clear.…”

“…The pool of PE-CAM-1 in LBRC is approximately 30% of the total (266). Neutrophils in PECAM-1 -/ -mice become impacted between endothelial cells and basement membrane in IL-1b-stimulated mice, indicating that PECAM-1 is essential for the neutrophil to traverse the junctions (458). Interestingly, the role of JAM-A, PECAM1, and ICAM-2 in neutrophil migration appears to be stimulus dependent.…”

“…The deep penetration of neutrophils between endothelial cells is mediated by JAM-A (Fig. 7b), as neutrophils accumulate deeper down the junctions in JAM-A 2/2 mice treated with IL-1b (458). In the resting endothelium, PECAM-1 is stored along the cell borders in the intracellular compartment known as lateral border recycling compartment (LBRC) and translocates to the site of diapedesis when leukocyte migration occurs (Fig.…”

β2 Integrin–Mediated Crawling on Endothelial ICAM-1 and ICAM-2 Is a Prerequisite for Transcellular Neutrophil Diapedesis across the Inflamed Blood–Brain Barrier

“…In addition, LFA-1-mediated crawling of neutrophils has previously been described on immobilized ICAM-1 in vitro (47). As different proinflammatory stimuli were found to induce different molecular mechanisms of neutrophil interaction with vascular endothelium in vivo (56), the involvement of LFA-1 versus Mac-1 in mediating neutrophil crawling might depend on the inflammatory status of the respective endothelial cells and thus the density of the endothelial b 2 integrin ligands ICAM-1, ICAM-2, and JAM-A. In addition, a major contribution of Mac-1 in mediating neutrophil crawling might also depend on the activation status of the neutrophil itself (56).…”

Neutrophil Chemotaxis and Polarization: When Asymmetry Means Movement

“…A number of molecules at EC junctions actively facilitate leukocyte transmigration via a paracellular route such as Platelet endothelial adhesion molecular-1 (PECAM-1), Intracellular adhesion molecule-2 (ICAM-2), CD99, Endothelial cell-selective adhesion molecules (ESAM), and junctional adhesion molecules (JAM) [22,26] and, according to in vivo and in vitro evidence, a sequence of events has been suggested that regulate neutrophil transmigration to EC walls and that include the following: (i) ICAM-1 and ICAM-2 on the luminal surface of EC and within the junction may provide a haptotactic gradient to guide neutrophils to EC junctions via their 2 partners (LFA-1 and MAC-1) [27]; (ii) once within junctions, endothelial-cell JAM-A (through interaction, possibly with LFA-1) [28], facilitates completion of neutrophil passage through the EC layer, and (iii) within the EC junction, homophilic interactions between endothelial and leukocyte PECAM-1 stimulates neutrophils to express the key leukocyte laminin receptor, integrin 6 1, on their surface, which facilitates neutrophil passage through the vascular basement membrane [29][30][31]. It is also noteworthy that signals from ICAM-1 activate Src and Pyk-2 tyrosine kinases, which phosphorylate VE-Cadherin, destabilizing its bonds and loosening endothelial cell-cell junctions [32].…”