JAM-C regulates unidirectional monocyte transendothelial migration in inflammation

Abstract

IntroductionTargeting leukocyte migration from the vasculature to sites of inflammation requires a series of coordinated adhesive interactions. 1 Of particular interest are molecules distributed at endothelial junctions, where cis-and trans-interactions allow endothelial cells (ECs) to interact with and regulate leukocyte migration into underlying tissues.Junctional adhesion molecules (JAMs) encompass a family of 6 immunoglobulin-like proteins: CAR, ESAM, JAM4, JAM-A, JAM-B, and JAM-C. 2,3 Differential expression and redistribution of JAM-B and JAM-C at the endothelial junction contribute to leukocyte interactions and trafficking. 4 Endothelial cell JAM-C preferentially interacts with JAM-B, forming a 2-dimensional network of both molecules localized at endothelial junctions. [4][5][6] Complex hierarchies dictate how JAM-B/-C multimers interact with integrin counterreceptors. JAM-B can bind the integrin VLA-4 (␣ 4 ␤ 1 ; CD29a/CD49d), but requires prior engagement with JAM-C, 7 whereas JAM-C can act as a counterreceptor for the integrin Mac-1 (␣ M ␤ 2 ; CD11b/CD18) independently of Although JAM-C is expressed by fibroblasts 9 and epithelial cells, 10-12 the role of endothelial JAM-C in leukocyte accumulation during inflammation 13 has received particular attention. In humans, JAM-C is expressed on circulating platelets, natural killer (NK) cells, dendritic cells, and subsets of T and B cells, 4,7,14-16 but not on circulating mouse leukocytes. 5 Preliminary studies with functional blocking antibodies to JAM-C showed reduced transmigration of peripheral blood lymphocytes across cultured human umbilical vein endothelial cells (HUVECs), 15 and later studies identified Mac-1 as a ligand partner that can mediate adhesion and transmigration for neutrophils and monocytes and transepithelial migration of neutrophils. 8,10,17,18 Numerous studies have addressed this dual functionality of JAM-C as an adhesion and transmigration regulatory molecule. Experimental animal models of inflammation support a role for JAM-C in regulating leukocyte accumulation within inflammatory lesions. Soluble JAM-C (solJAM-C) and antibodies to JAM-C inhibit leukocyte emigration in mouse models of inflammation. 5,17 In addition, in mouse models of allergic contact dermatitis, the regulatory role of JAM-C in inflammation has also been associated with modulation of JAM-B/-C interactions, where combined blocking antibodies to JAM-B and JAM-C had an additive effect on blocking leukocyte recruitment. 19 Furthermore, recent reports have identified additional steps requiring the disruption/engagement of the JAM-B/-C complex, before the respective integrin counterreceptor is engaged. 6,7 In this study, we have developed a flow assay that allows detailed analysis of individual monocyte interactions with ECs. This analysis can begin at the initial phase of capture from free-flow under physiologic conditions and continue to posttransmigrational events. Using this model, we elucidated a novel role for endothelial JAM-C in regulating monocyte retention in t...

Homing of Human B Cells to Lymphoid Organs and B-Cell Lymphoma Engraftment Are Controlled by Cell Adhesion Molecule JAM-C

“…These cells constitute the major populations of circulating B cells in the peripheral blood compartment. Because JAM-C plays an important role in neutrophil and monocyte migration (19,20), we investigated whether JAM-C could also influence the migration of circulating B cells to lymphoid organs.…”

Endothelial Junctional Adhesion Molecule-A Guides Monocytes Into Flow-Dependent Predilection Sites of Atherosclerosis

“…This retentive control exerted by JAM-A complements a reverse gate-keeper function revealed for JAM-C in a study in which blocking JAM-C reduced the number of monocytes in inflammatory tissue by increasing reverse transmigration. 35 Accordingly, a hesitant or reverse transmigration behavior has been identified for neutrophils during inflammation after ischemia-reperfusion injury in vivo, which was characterized by lower expression of JAM-C at endothelial junctions, enhanced by blockade or genetic deletion of JAM-C 36 , and implicated in systemic dissemination of inflammation.…”

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

“…26,35,36 Such a cascade of events is supported by data presented here demonstrating that blockers of both Mac-1 and JAM-C can suppress leukocyte transmigration elicited by TNF-␣, some in agreement with previous studies. 20 Of importance, as the precise mechanism of action of JAM-C in mediating leukocyte transmigration remains unclear, 20,37 eg, it is unclear to what extent JAM-Cmediated leukocyte transmigration in vivo is mediated through its interactions with Mac-1 and/or JAM-B, 37,38 details of the components and cascade of molecular events that mediate leukocyte transmigration as elicited by TNF-␣ require further investigations. Collectively, the present results do, however, provide direct in vivo evidence to indicate that activation of EC and leukocyte TNF-␣ receptors may act in sequence to mediate leukocyte firm adhesion and transmigration, respectively ( Figure 6A).…”

“…15 Leukocyte adhesion and transmigration responses were quantified in postcapillary venules as previously detailed. 15 In some experimental groups, mice were pretreated with intravenous saline, an isotype control mAb, or blocking mAbs directed against ICAM-2 (3C4), 14 (BD Biosciences, Oxford, United Kingdom), JAM-A (BV-11), 18 PECAM-1 (Mec13.3; BD Biosciences), Mac-1 (56C), 19 and JAM-C (H33), 20 (all at 1-5 mg/kg, as indicated in appropriate legends, for maximal inhibitory effect), 15 minutes before the induction of inflammatory reactions.…”