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  • Review Article
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The role of junctional adhesion molecules in vascular inflammation

Nature Reviews Immunology volume 7, pages 467–477 (2007)Cite this article

Key Points

  • Junctional adhesion molecules (JAMs) are expressed by leukocytes, platelets, endothelial and epithelial cells. JAMs are important in the control of vascular permeability and leukocyte transmigration across endothelial-cell surfaces.

  • JAMs engage in homophilic interactions and various heterophilic interactions with the leukocyte integrins lymphocyte function-associated antigen 1 (LFA1), very late antigen 4 (VLA4) and MAC1.

  • JAMs are upregulated under inflammatory, atherosclerotic or ischaemic conditions. JAMs are redistributed from intercellular junctions to the cell surface after inflammatory stimulation.

  • Both endothelial-cell and leukocyte JAM-A contribute in a molecular 'zipper' that controls transendothelial diapedesis, whereas JAM-C supports leukocyte adhesion on platelets and subsequent transendothelial migration. Both JAM-A and JAM-C promote leukocyte recruitment on activated endothelium under inflammatory conditions.

  • Studies using genetically modified mice have shown important roles for JAMs in the regulation of leukocyte recruitment to sites of inflammation, ischaemia–reperfusion injury, atherogenesis, and in neointima formation.

  • JAMs are involved in growth-factor-mediated angiogenesis by association with αvβ3-integrin and subsequent signalling steps.

Abstract

Junctional adhesion molecules (JAMs) of the immunoglobulin superfamily are important in the control of vascular permeability and leukocyte transmigration across endothelial-cell surfaces, by engaging in homophilic, heterophilic and lateral interactions. Through their localization on the endothelial-cell surface and expression by platelets, JAMs contribute to adhesive interactions with circulating leukocytes and platelets. Antibody-blocking studies and studies using genetically modified mice have implicated these functions of JAMs in the regulation of leukocyte recruitment to sites of inflammation and ischaemia–reperfusion injury, in growth-factor-mediated angiogenesis, atherogenesis and neointima formation. The comparison of different JAM-family members and animal models, however, shows that the picture remains rather complex. This Review summarizes recent progress and future directions in understanding the role of JAMs as 'gate keepers' in inflammation and vascular pathology.

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Figure 1: Structural features of the JAM-family members and a molecular model for JAM homophilic adhesion.
Figure 2: Cellular expression and extracellular ligands of JAMs.
Figure 3: Molecular models of JAM-A and JAM-C in leukocyte adhesion and transmigration.
Figure 4: JAMs in angiogenesis, ischaemia–reperfusion injury, atherogenesis and arterial injury.

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Acknowledgements

The authors thank R. R. Koenen for helpful discussions and E. A. Liehn for help with immunofluorescence.

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  1. Institute for Molecular Cardiovascular Research, RWTH University Hospital, Aachen, 52074, Germany

    Christian Weber & Line Fraemohs

  2. FIRC Institute of Molecular Oncology and Department of Biomolecular and Biotechnological Sciences, University of Milan, Milan, 20139, Italy

    Elisabetta Dejana

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Glossary

Adherens junctions

Specialized intercellular junctions of the plasma membrane, in which the cadherin molecules at the surface of adjacent cells interact in a calcium-dependent manner. Actin filaments are linked to these cadherin structures through catenin molecules that are located beneath the junctions.

Tight junctions

A belt-like region of adhesion between adjacent epithelial or endothelial cells that regulates paracellular flux. Tight-junction proteins include the integral membrane proteins occludin and claudin, in association with cytoplasmic zonula occludins proteins.

High endothelial venule

A specialized venule that occurs in secondary lymphoid organs, except the spleen. HEVs allow continuous transmigration of lymphocytes as a consequence of the constitutive expression of adhesion molecules and chemokines at their luminal surface.

Desmosome

An adhesive junction that connects epithelial cells in stratified squamous tissues. These junctions are composed of multiple protein subunits and are the points where keratin filaments are inserted into the plasma membrane.

Haptotactic gradient

A substrate-bound gradient that promotes directed migration of adherent cells.

Atherosclerotic plaque

An atherosclerotic lesion consisting of a fibrotic cap surrounding a lipid-rich core. The lesion is the site of inflammation, lipid accumulation and cell death. It is also known as an atheroma.

Ischaemia–reperfusion injury

An injury in which the tissue first suffers from hypoxia as a result of severely decreased, or completely arrested, blood flow. Restoration of normal blood flow then triggers inflammation, which exacerbates the tissue damage.

Surface plasmon resonance

The detection of alterations in plasmon waves generated at a metal–liquid interface. Changes in surface plasmon resonance are a function of the mass of molecules bound to the interface, so this technique allows sensitive detection of ligand binding in real time without requiring the chemical modification of ligands to enable their detection.

Vascular endothelial cadherin

An endothelial-cell-specific cadherin (adhesive protein) that is present in adherens junctions, which are located between endothelial cells.

Pseudopod

A temporary projection of the cytoplasm of certain cells, such as neutrophils, or of certain unicellular organisms, especially amoebae, that functions in locomotion.

Uropod

A slender protrusion that forms at the rear end of migrating leukocytes.

Neointima

The innermost layer of an artery, which is covered by a monolayer of endothelium, is termed the intima. Atherosclerotic plaques form in the intima. A neointima forms after arterial denudation injury comprising a new layer of endothelial cells on the intimal surface.

Atherothrombosis

Following the rupture of unstable atherosclerotic plaques, thrombogenic material becomes exposed or released to mediate thrombus formation and eventually occlusion of an artery.

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Weber, C., Fraemohs, L. & Dejana, E. The role of junctional adhesion molecules in vascular inflammation. Nat Rev Immunol 7, 467–477 (2007). https://doi.org/10.1038/nri2096

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