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Originally published online as doi:10.1189/jlb.1105645 on July 20, 2006

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(Journal of Leukocyte Biology. 2006;80:714-718.)
© 2006 by Society for Leukocyte Biology

The role of JAM-A and PECAM-1 in modulating leukocyte infiltration in inflamed and ischemic tissues

Sussan Nourshargh*, Fritz Krombach{dagger} and Elisabetta Dejana{ddagger},§,¶,1

* Cardiovascular Medicine Unit, National Heart and Lung Institute, Imperial College London, London, United Kingdom;
{dagger} Institute for Surgical Research, University of Munich, Munich, Germany;
{ddagger} FIRC Institute of Molecular Oncology, Milan Italy;
§ Department of Biomolecular and Biotechnological Sciences, School of Sciences, University of Milan, Milan, Italy; and
Mario Negri Institute of Pharmacological Research, Milan, Italy

1 Correspondence: IFOM, FIRC Institute of Molecular Oncology, Via Adamello 16, Milan 20139, Italy. E-mail: elisabetta.dejana{at}ifom-ieo-campus.it

ABSTRACT

Innate and adaptive immunological responses are accompanied by leukocyte adhesion to the blood-vessel wall and their subsequent infiltration into the underlying tissues. In the majority of the cases, leukocytes cross the endothelium by squeezing through the border of apposed endothelial cells, a process that is known as diapedesis. Many data suggest that proteins at endothelial junctions establish homophilic interactions with identical proteins, which are present on leukocytes. These interactions might then direct the passage of leukocytes through the endothelial border. In this review, we focus on two endothelial junctional proteins [junctional adhesion molecule-A (JAM-A) and PECAM], which play an important role in leukocyte diapedesis. In vivo data with blocking antibodies or inactivation of JAM-A and PECAM genes indicate that the role of these two proteins depends on the stimulus and the experimental model used.

Key Words: inflammation • ischemia • endothelium

INTRODUCTION

The capacity of leukocytes to arrest on the surface of inflamed endothelium, diapedese, and penetrate into the underlying stroma is a key step in the response to infections. In addition, in conditions of tissue ischemia-reperfusion, neutrophils exit the circulation and infiltrate into the ischemic regions. The knowledge of the mechanisms that regulate these processes is important to control and eventually limit inflammatory reactions or tissue damage (for reviews, see refs. [1 2 3 4 5 ]). As a result, the response of neutrophil migration into inflamed tissues is now considered as a prime target for the development of novel therapeutic interventions and thus, has triggered a tremendous interest in dissecting the molecular interactions that mediate and regulate this process.

Neutrophils arrest on and traverse the endothelium through the action of adhesive receptors. Elaborate in vitro and in vivo studies have indicated that the initial events in this response involve weak adhesive interaction of leukocytes with the vessel wall, termed tethering and rolling, a response mediated largely by the action of selectins. This is followed by the firm adhesion of leukocytes, mediated by integrins, and migration through the endothelial cell barrier [6 ]. We have only a partial knowledge of the mechanisms that govern this last process and of the molecules involved. It is believed that in the majority of cases, leukocytes follow the "paracellular" pathway; i.e., they traverse the endothelium through cell-to-cell junctions. Recent papers suggest that leukocytes can also use the "transcellular pathway"; i.e., they can use a vesicular/canalicular system to cross cytoplasm of single endothelial cells [7 , 8 ].

Proteins at cell-to-cell junctions, in particular, PECAM-1 and junctional adhesion molecules (JAMs), have been shown to play an important role in controlling the paracellular pathway, i.e., leukocyte movement through endothelial junctions [1 , 3 , 9 , 10 ]. In this brief review, we summarize the data we collected in our labs using different experimental systems of inflammation and tissue ischemia-reperfusion. Our focus is on the role of JAM-A and PECAM-1, as others in the same issue discuss the role of JAM-B and -C. Taken together, our data show that JAM-A and PECAM-1 play important roles in mediating leukocyte transmigration through endothelial cells, although their contribution to this response appears to be governed very much by the nature of the inflammatory model under investigation.

JAM-A

JAM-A is a small Ig present in leukocytes, platelets, and endothelial and epithelial cells [1 , 2 , 10 ]. In endothelial and epithelial cells, it is particularly enriched at intercellular junctions and more specifically, at tight junctions. JAM-A may exert multiple actions, which are likely mediated by different intracellular partners [11 ]. Through the last three amino acids of the cytoplasmic tail, JAM-A can bind to PSD-95/Disc Large/zona occludens protein-1 (ZO-1; PDZ)-containing proteins, which may mediate the anchorage to actin microfilaments; ALL-1 gene fusion partner (AF-6)/afadin, which may bind Ras-like G protein (Rap-1), which in turn, may modulate integrin and cadherin adhesive properties [12 13 14 ]; proteinase-activated receptor 3 (PAR3)–PAR6, an atypical protein kinase C (PKC) complex, which was found to determine cell polarity in other cell types; and multi-PDZ domain protein-1 and calmodulin-associated serine/threonine kinase, which may have different biological activities [1 , 2 , 10 ]. It is interesting that JAM-A concentrates at intercellular contacts at an early stage of junction organization, suggesting that it is required as a first step for a further, more complex organization of junctions [14 ].

Blocking antibodies or inactivation of the JAM-A gene prevent inflammatory reactions in vivo [11 , 15 16 17 18 ]. As summarized in Table 1 , blocking JAM-A activity or expression caused a decrease in neutrophil or monocyte extravasation in inflammatory meningitis, peritonitis, skin or cremaster microcirculation, ischemia-reperfusion of heart and liver. In liver and heart ischemia-reperfusion, JAM-A–/– neutrophils remain on the vascular surface and, in some cases, form aggregates. Their permanence on the endothelial surface and the release of oxygen species and lytic enzymes may cause tissue damage. Indeed, tissue injury after ischemia is more pronounced in JAM-A null mice despite reduced numbers of infiltrating cells [15 , 17 ].


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  		Table 1. Effect of JAM-A Inhibition on Different Models of Inflammation or Ischemia-Reperfusion Injury

 
An important but still not completely clarified aspect is the mechanism of action of JAM-A in promoting leukocyte extravasation. Endothelial JAM-A may direct the movement of leukocytes through cell-cell junctions by homophilic interaction with JAM-A expressed on the leukocyte membrane [21 ]. Alternatively, endothelial JAM-A may promote leukocyte adhesion and extravasation through binding to leukocyte LFA-1 [22 ]. However, although activated neutrophils transmigrating through cytokine-stimulated endothelial cells under flow exhibit coclustering of ICAM-1 with LFA-1, endothelial JAM-A does not cocluster with LFA-1 [23 ]. These findings suggest that JAM-A is not a ligand for LFA-1 and/or only supports leukocyte transmigration under specific experimental conditions, inflammatory stimuli, and/or with certain cell types (see below). JAM-A is also present in leukocytes. Recent work showed that JAM-A is required for neutrophil directional motility [17 ]. Neutrophils derived from mice in which JAM-A has been deleted genetically are unable to migrate correctly through endothelial cell junctions in vivo. In vitro, they move less efficiently toward a chemotactic stimulus, actin organization and cell polarization are strongly affected. This is accompanied by increased adhesion to endothelial cells and matrix proteins, which prevent their correct movement.

Thus, JAM-A is required for movement of leukocytes toward the site of inflammation. However, the mechanism of action of this protein is still a matter of investigation. One possibility is that through its partners, in particular, Rap-1 (which may interact with JAM-A through AF-6, see above) or PAR3/PAR6, a PKC complex, JAM-A may contribute to integrin dynamic activation/inactivation and cytoskeletal organization during leukocyte chemotaxis (for review, see refs. [1 , 12 , 13 ]). Dendritic cells also express JAM-A. In vitro, JAM-A null dendritic cells showed a selective increase in random motility and in their capacity to transmigrate across lymphatic endothelial cells. In vivo, in JAM-A null mice, dendritic cells migrated more effectively to lymph nodes, a response that was associated with enhanced contact hypersensitivity [19 ]. Collectively, it is therefore possible that the consequences of JAM-A targeting are versatile in different cell types and tissues, depending on the site of cell diapedesis (lymphatics vs. blood vessels) and/or the coexistence of other members of the JAM family.

Besides leukocyte extravasation, endothelial JAM-A may play a role in angiogenesis, likely through its regulation of cell movement [24 ]. Specifically, it has been shown that in endothelial cells, JAM-A can interact with ß3 integrins and modulate their motility and the organization of vascular structures. In the absence of JAM-A, endothelial cells move more rapidly but in a random way and lose directionality [25 ]. JAM-A null mice did not show, however, major problems in the development of the vascular system or in vascular or epithelial permeability. This suggests that other proteins, such as other members of the JAM family, endothelial cell-selective adhesion molecule (ESAM) or PECAM-1, may substitute JAM-A for junction organization or endothelial motility.

In conclusion, JAM-A, through its manifold activities in different cell types, may play an important role in inflammatory or immune reactions. It is noteworthy, however, that JAM-A inhibition/deletion is not effective in all models, and preliminary data suggest that the functional role of JAM-A may be stimulus-dependent. Endothelial JAM-A may be up-regulated by ischemia in vivo as reported for the microcirculation of the liver [15 ], suggesting a further control of its activity in certain vascular beds. In addition, JAM-A localization at endothelial cell intercellular junctions may be altered following cell activation with certain inflammatory cytokines [26 ], an effect that may modulate leukocyte migration through endothelial cells. Overall, these observations suggest that JAM-A activity may be regulated by neosynthesis or redistribution on the endothelial cell membrane, indicating that its blockade may be effective in some but not all inflammatory or ischemic conditions.

PECAM-1

Like JAM-A, PECAM-1 (CD31) is a member of the Ig gene superfamily. PECAM-1 is composed of six extracellular Ig folds, has a molecular weight of 130 kDa, and is glycosylated differentially involving N-linked and O-linked glycosylation sites. PECAM-1 is expressed at high density at the lateral borders of endothelial cells and at a lower density on the surface of hematopoietic and immune cells, including macrophages, neutrophils, monocytes, mast cells, natural killer cells, lymphocytes, and platelets [3 ]. In common with other cell adhesion molecules, PECAM-1 has important signaling properties and as a result, has been associated with numerous biological responses, including angiogenesis, immune functions, and platelet aggregation [27 ]. However, arguably, its claim to fame is as a result of its significant role in leukocyte transendothelial migration.

Muller and colleagues [28 ] first reported about the functional role of PECAM-1 in leukocyte transendothelial cell migration in 1993. In this paper, in vitro studies showed that blockers of PECAM-1 suppressed neutrophil transmigration through cytokine (IL-1ß and TNF-{alpha})-stimulated, cultured endothelial cells by ~80%. The first in vivo report about the role of PECAM-1 in leukocyte migration into inflamed tissues came from the group of Albelda and colleagues [29 ], in which anti-PECAM-1 antibodies were found to suppress neutrophil accumulation into inflamed peritoneum of rats, neutrophil accumulation into airways after local deposition of IgG immune complexes in rat lungs, and neutrophil accumulation induced by intradermal TNF-{alpha} into human skin grafts transplanted onto immunodeficient mice. First, direct evidence for the involvement of PECAM-1 in leukocyte transmigration through venular walls in vivo was obtained using the technique of intravital microscopy [30 , 31 ]. Of importance, these studies demonstrated that as well as mediating leukocyte migration through endothelial cells, PECAM-1 can also mediate leukocyte migration through the perivascular basement membrane. The details of the mechanisms by which PECAM-1 can mediate leukocyte migration through venular walls remain unclear, but there is now much evidence to suggest that a homophilic interaction between leukocyte PECAM-1 and endothelial cell PECAM-1 guides leukocytes through endothelial cell junctions [3 ]. Such an effect may be supported via enhanced expression of PECAM-1 at endothelial cell junctions during the transmigration process through recycling of PECAM-1-rich membrane invaginations below the plasma membrane at lateral junctions of endothelial cells, as recently suggested [32 ]. Furthermore, we have found that the ability of PECAM-1 to mediate leukocyte migration through the perivascular basement membrane is also mediated via homophilic PECAM-1 ligation, a response that is critical for enhanced expression of the integrin {alpha}6ß1 (principal leukocyte receptor for laminin) on the cell surface of transmigrating neutrophils [33 , 34 ].

Despite the strong in vitro and in vivo evidence implicating PECAM-1 in leukocyte migration through endothelial cell junctions, as obtained using anti-PECAM-1-blocking antibodies, initial studies performed on PECAM-1-deficient mice failed to detect a significant defect in leukocyte transendothelial cell migration [35 ]. Specifically, the most pronounced defect observed was suppression of leukocyte transmigration at the level of the venular basement membrane [35 , 36 ]. Recent studies have, however, reported more pronounced defects in leukocyte transmigration in two models of inflammation (thioglycollate-induced peritonitis and croton oil-induced topical dermatitis models) in PECAM-1-deficient animals when the mice were bred on mouse strains other than the C57BL/6 strain [37 ] (e.g., FVB/n strain). By indicating that the functions of PECAM-1 may be governed by the strain of the mouse used, these findings add a new layer of complexity to the biology of this molecule.

Findings with neutralizing anti-PECAM-1 antibodies in rats and PECAM-1-deficient mice (on the C57BL/6 background) also indicated a stimulus-specific role for PECAM-1 in that although leukocyte migration through venular walls elicited by IL-1ß was found to be PECAM-1-dependent, responses induced by TNF-{alpha} and the chemotactic peptide fMLP were PECAM-1-independent [30 , 31 ]. The reason for this stimulus-specific activation of the PECAM-1-dependent pathway is currently unclear but may be governed at multiple levels, e.g., the target cell being stimulated (leukocyte vs. endothelial cell), the type of inflammatory receptor, and hence, signaling pathways activated. The observed profiles seen may also be manifested as a result of the inflammatory models and/or the animal species/strains used, as detailed above. Of interest, however, the detected stimulus-specific profile of PECAM-1-dependent transmigration is directly in line with the observations recently made with respect to ICAM-2 [38 ] and also as indicated above, with JAM-A-dependent transmigration. The molecular basis of these observations is, at present, unclear. With respect to PECAM-1, however, as PECAM-1-dependent leukocyte transmigration is considered to be regulated via the ability of the PECAM-1/PECAM-1 interaction to activate (e.g., ß2 integrins) [27 ] and/or up-regulate ({alpha}6ß1) [33 , 34 ] leukocyte integrins, one may speculate that stimuli, which can stimulate leukocytes directly, can induce leukocyte transmigration in a PECAM-1-independent manner; i.e., the need for PECAM-1-mediated activation of integrin-dependent pathways is bypassed.

Collectively, although the evidence supporting a role for the involvement of PECAM-1 in leukocyte transmigration is strong, there exist clear indications of stimulus- and inflammatory model-specific scenarios determining the functions of this molecule. In addition, like JAM-A, the expression of PECAM-1 on endothelial cells has also been reported to be regulated by certain cytokine combinations and disease states [39 40 41 42 ]. Although the functional significance of such effects needs clarification, possible alterations in expression of vascular PECAM-1 in different inflammatory reactions could potentially lead to varied functional roles of this molecule in the process of leukocyte trafficking. Furthermore, it is, at present, unclear as to whether the temporal phase of an inflammatory reaction can govern PECAM-1 dependency or independency. These issues could have implications to the magnitude and nature of how PECAM-1 could mediate leukocyte transmigration in different inflammatory disease states—issues that need to be further investigated as part of future studies.

CONCLUSIONS

As summarized above, JAM-A and PECAM-1 share many structural and functional properties. They are members of the Ig family, concentrate at intercellular junctions, are expressed by leukocytes and endothelial cells, and most importantly, can both mediate leukocyte diapedesis. However, in this context, key functional roles of these molecules can often be detected only when using specific stimuli or animal models, suggesting that in some conditions, PECAM-1 and JAM-A may exert a redundant role. In addition, other proteins, such as other members of the JAM family—CD99 and ESAM molecules found at endothelial cell borders and capable of mediating leukocyte transmigration—may support PECAM-1/JAM-A-independent leukocyte diapedesis. Overall, the current available data highlight the complexity of the process of leukocyte diapedesis through endothelial cells, indicating the involvement of different mechanisms depending on the pathological condition and/or the specific vascular bed in question. Future studies using mice carrying null mutations for more than one junctional protein would be useful to understand whether the activity of molecules such as JAM-A and PECAM-1 are complementary, additive, or synergistic.

ACKNOWLEDGEMENTS

This work was supported by the European Community (QLRT-2001-02059, Integrated Project Contract No. LSHG-CT-2004-503573; NoE MAIN 502935; NoE EVGN 503254) and the Associazione Italiana per la Ricerca sul Cancro (AIRC).

Received November 10, 2005; revised April 29, 2006; accepted May 7, 2006.

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