Platelet endothelial cell adhesion molecule-1 (PECAM-1 or CD31) is a molecule expressed on all cells within the vascular compartment, being expressed to different degrees on most leukocyte sub-types, platelets, and on endothelial cells where its expression is largely concentrated at junctions between adjacent cells. As well as exhibiting adhesive properties, PECAM-1 is an efficient signaling molecule and is now known to have diverse roles in vascular biology including roles in angiogenesis, platelet function, and thrombosis, mechanosensing of endothelial cell response to fluid shear stress, and regulation of multiple stages of leukocyte migration through venular walls. This review will focus on some new developments with respect to the role of PECAM-1 in inflammation and vascular biology, highlighting the emerging complexities associated with the functions of this unique molecule.

PECAM-1: A Multi-Functional Molecule in Inflammation and Vascular Biology

The proper function of immune surveillance requires well-coordinated mechanisms in order to guide the patrolling immune cells through peripheral tissues and into secondary lymphoid organs. Analyzing gene-targeted mice, we identified the chemokine receptor CCR7 as an important organizer of the primary immune response CCR7-deficient mice show severely delayed kinetics regarding the antibody response and lack contact sensitivity and defayed type hypersensitivity reactions. Due to the impaired migration of lymphocytes, these animals reveal profound morphological alterations in all secondary lymphoid organs, Upon activation, mature skin dendritic cells fad to migrate into the draining lymph nodes. Thus, in order to bring together lymphocytes and dendritic cells to form the characteristic microarchitecture of secondary lymphoid organs, CCR7 is required to rapidly initiate an adoptive immune response.

CCR7 Coordinates the Primary Immune Response by Establishing Functional Microenvironments in Secondary Lymphoid Organs (Reprinted from Cell, vol 99, pg 23-33, 1999)

The present study aimed to demonstrate constitutive expression of the intercellular adhesion molecule (ICAM)-1 among arterioles, capillaries, and venules in the mesentery and liver and to examine the interaction between cultured endothelial cells and leukocytes in rats. ICAM-1 expression in the microvessels in vivo was visually demonstrated by laser confocal fluorescence microscopy. A monoclonal antibody against rat ICAM-1 (1A29) was labeled with fluorescein isothiocyanate, and the binding ratio between the fluorescence and immunoglobulin was determined for data calibration. Intravascularly administered fluorescein isothiocyanate-labeled 1A29 was distributed heterogeneously among the hierarchy of microvessels in the mesentery: postcapillary venules were the major portion expressing ICAM-1 constitutively, and the density of 1A29 bound to their endothelium was at least 10 times higher than that in true capillaries and arterioles in the same mesentery. On the other hand, the liver expressed ICAM-1 abundantly in sinusoids to the extent similar to that in central venules. These results suggest that postcapillary venules serve as an active gateway with the readiness to help adhere circulating leukocytes exposed to proinflammatory stimuli in acute inflammation.

Constitutive expression of ICAM-1 in rat micrevascular systems analyzed by laser confocal microscopy.

Objectives— Leukocyte migration through venular walls is a fundamental event during inflammation, but many aspects of this response, including the mechanisms associated with leukocyte migration through the vascular basement membrane (BM) in vivo, are poorly understood. Here we investigated and compared the means by which neutrophils and monocytes migrate through the venular BM. Specifically, as we have previously reported on the existence of neutrophil permissive sites (termed matrix protein low expression regions; LERs) within the venular BM, we have now investigated the role of these sites in monocyte transmigration in vivo. Methods and Results— Analysis of CCL2-stimulated mouse cremaster muscles by immunofluorescent staining and confocal microscopy demonstrated that both neutrophils and monocytes use LERs for penetrating venular walls, but independent and distinct mechanisms are used by the 2 cell types. Collectively, (1) neutrophil but not monocyte transmigration led to enlargement of LERs, (2) monocy...

Monocytes and Neutrophils Exhibit Both Distinct and Common Mechanisms in Penetrating the Vascular Basement Membrane In Vivo

Exclusive increase of CX3CR1[+]CD28[-]CD4[+] T cells in inflammatory bowel disease and their recruitment as intraepithelial lymphocytes

Mucosal addressin cell adhesion molecule-1 (MAdCAM-1) is a tissue–specific protein that promotes α4β7+ lymphocyte recruitment on gut mucosal endothelium, playing an important role in the development of inflammatory bowel disease (IBD). Recent studies have reported its expression in liver diseases such as primary sclerosing cholangitis (PSC) and autoimmune hepatitis (AIH) that complicate IBD, therefore understanding the factors that drive hepatic expression of MAdCAM-1 might elucidate the pathogenesis of these diseases. In vitro stimulation of HSEC with tumor necrosis factor-α (TNFα) and methylamine, the physiological substrate of vascular adhesion protein-1 (VAP-1), as well as with the end products of methylamine deamination by VAP-1, resulted in increased levels of secreted and cell surface MAdCAM-1 protein that was able to support binding of α4β7+ lymphocytes under flow conditions. In vivo stimulation of mice that expressed hVAP-1 as a transgene, with methylamine, induced expression of MAdCAM-1 in Peyer’s patches and mesenteric lymph nodes, validating the effect of VAP-1 enzyme activity. In conclusion, we report for the first time that MAdCAM-1 is normally present in human liver and is further induced upon TNFα and methylamine stimulation resulting in the recruitment of mucosal cells to the liver, thus sustaining a destructive inflammatoty influx responsible for the establishment of chronic inflammation.

MAdCAM-1 expression and function in human liver.

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MAdCAM-1 expression and function in human liver.