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Junctional adhesion molecules, versatile players in inflammatory immune reactions

English title Junctional adhesion molecules, versatile players in inflammatory immune reactions
Applicant Imhof Beat A.
Number 135701
Funding scheme Project funding
Research institution Département de Pathologie et Immunologie Faculté de Médecine / CMU Université de Genève
Institution of higher education University of Geneva - GE
Main discipline Immunology, Immunopathology
Start/End 01.04.2011 - 31.03.2014
Approved amount 679'165.00
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Keywords (6)

Endothelium; cell adhesion; leukocyte migration; adhesion molecule; cell junctions; angiogenesis

Lay Summary (English)

Lead
Lay summary

LEAD

Adhesion molecules stabilize the cell-cell contacts in endothelial barriers. Junctional adhesion molecules B and C (JAMB, JAMC)are part of a network of proteins controlling this physical barrier by preserving endothetial polarity between the luminal and abluminal membrane domains. The Jam interactions will be studied in leukocyte migration during inflammation, autoimmunity and neovessel formation.

RESUME

The vascular molecules JAM-B and-C, previously cloned by our laboratory, are expressed by vascular endothelial cells and they control vascular permeability, cell polarity, inflammatory leukocyte transmigration and angiogenic neovessel formation. We found that JAM-B and -C interact with high affinity. However, our trustable techniques did not confirm several described other binding partners such as the leukocyte integrins and others. As we are convinced that such complex interactions between leukocytes andothelial JAMs exist, we will search for Jam ligands by various methods including the so called two hybrid system. We hope that these novel ligands will be of help to explain why JAMs contribute to the one-way traffic of leukocytes into inflamed tissue and what signal transduction mechanisms prevail. Using our valuable reagents we then will study the role of the JAMs in models for multiple sclerosis (MS), B cell leukemia and tumor angiogenesis.

BUT

This project will elucidate novel molecular machanisms leading to understand chronic inflammatory reactions and in particular leukocyte migration across the vascular barrier. As JAMs control endothelial junctions our work should also be able to explain their role in the angiogenic formation of novel blood vessels, for example during tumor progression and embryogenesis

SIGNIFICATION

This type of research investigates the basic molecular mechanisms how JAM-B and_c determine vital vascular functions. They include vascular permeability, leukocyte transmigration during inflammation and angiogenesis. The project then turns towards investigations of more complex pathologies such as multiple sclerosis or leukemia . Data collected with animal models not only should explain basic mechanisms but rather will guide us towards developing therapies in human.

 

Direct link to Lay Summary Last update: 21.02.2013

Responsible applicant and co-applicants

Employees

Publications

Publication
Aortic aneurysm, CCN3 may solve the problem.
Emre Yalin, Imhof Beat A (2016), Aortic aneurysm, CCN3 may solve the problem., in Journal of thoracic disease, 8(9), 1025-1027.
Divergent JAM-C Expression Accelerates Monocyte-Derived Cell Exit from Atherosclerotic Plaques.
Bradfield Paul F, Menon Arjun, Miljkovic-Licina Marijana, Lee Boris P, Fischer Nicolas, Fish Richard J, Kwak Brenda, Fisher Edward A, Imhof Beat A (2016), Divergent JAM-C Expression Accelerates Monocyte-Derived Cell Exit from Atherosclerotic Plaques., in PloS one, 11(7), 0159679-0159679.
Blocking junctional adhesion molecule C enhances dendritic cell migration and boosts the immune responses against Leishmania major.
Ballet Romain, Emre Yalin, Jemelin Stéphane, Charmoy Mélanie, Tacchini-Cottier Fabienne, Imhof Beat A (2014), Blocking junctional adhesion molecule C enhances dendritic cell migration and boosts the immune responses against Leishmania major., in PLoS pathogens, 10(12), 1004550-1004550.
Immunological aspects of atherosclerosis.
Garrido-Urbani S, Meguenani M, Montecucco F, Imhof B A (2014), Immunological aspects of atherosclerosis., in Seminars in immunopathology, 36(1), 73-91.
Tight junction dynamics: the role of junctional adhesion molecules (JAMs).
Garrido-Urbani S, Bradfield P F, Imhof B A (2014), Tight junction dynamics: the role of junctional adhesion molecules (JAMs)., in Cell and tissue research, 355(3), 701-15.
Blockade but not overexpression of the junctional adhesion molecule C influences virus-induced type 1 diabetes in mice.
Christen Selina, Coppieters Ken, Rose Kerstin, Holdener Martin, Bayer Monika, Pfeilschifter Josef M, Hintermann Edith, von Herrath Matthias G, Aurrand-Lions Michel, Imhof Beat A, Christen Urs (2013), Blockade but not overexpression of the junctional adhesion molecule C influences virus-induced type 1 diabetes in mice., in PloS one, 8(1), 54675-54675.
Homing of human B cells to lymphoid organs and B-cell lymphoma engraftment are controlled by cell adhesion molecule JAM-C.
Doñate Carmen, Ody Christiane, McKee Thomas, Ruault-Jungblut Sylvie, Fischer Nicolas, Ropraz Patricia, Imhof Beat A, Matthes Thomas (2013), Homing of human B cells to lymphoid organs and B-cell lymphoma engraftment are controlled by cell adhesion molecule JAM-C., in Cancer research, 73(2), 640-51.
Three-dimensional visualization of the mouse thymus organization in health and immunodeficiency.
Irla Magali, Guenot Jeanne, Sealy Gregg, Reith Walter, Imhof Beat A, Sergé Arnauld (2013), Three-dimensional visualization of the mouse thymus organization in health and immunodeficiency., in Journal of immunology (Baltimore, Md. : 1950), 190(2), 586-96.
Thymic epithelial cell expansion through matricellular protein CYR61 boosts progenitor homing and T-cell output.
Emre Yalin, Irla Magali, Dunand-Sauthier Isabelle, Ballet Romain, Meguenani Mehdi, Jemelin Stephane, Vesin Christian, Reith Walter, Imhof Beat A (2013), Thymic epithelial cell expansion through matricellular protein CYR61 boosts progenitor homing and T-cell output., in Nature communications, 4, 2842-2842.
Targeting olfactomedin-like 3 inhibits tumor growth by impairing angiogenesis and pericyte coverage.
Miljkovic-Licina Marijana, Hammel Philippe, Garrido-Urbani Sarah, Lee Boris P-L, Meguenani Mehdi, Chaabane Chiraz, Bochaton-Piallat Marie-Luce, Imhof Beat A (2012), Targeting olfactomedin-like 3 inhibits tumor growth by impairing angiogenesis and pericyte coverage., in Molecular cancer therapeutics, 11(12), 2588-99.
Targeting vascular NADPH oxidase 1 blocks tumor angiogenesis through a PPARα mediated mechanism.
Garrido-Urbani Sarah, Jemelin Stephane, Deffert Christine, Carnesecchi Stéphanie, Basset Olivier, Szyndralewiez Cédric, Heitz Freddy, Page Patrick, Montet Xavier, Michalik Liliane, Arbiser Jack, Rüegg Curzio, Krause Karl Heinz, Imhof Beat A, Imhof Beat (2011), Targeting vascular NADPH oxidase 1 blocks tumor angiogenesis through a PPARα mediated mechanism., in PloS one, 6(2), 14665-14665.
The junctional adhesion molecule JAM-C regulates polarized transendothelial migration of neutrophils in vivo.
Woodfin Abigail, Voisin Mathieu-Benoit, Beyrau Martina, Colom Bartomeu, Caille Dorothée, Diapouli Frantzeska-Maria, Nash Gerard B, Chavakis Triantafyllos, Albelda Steven M, Rainger G Ed, Meda Paolo, Imhof Beat A, Nourshargh Sussan (2011), The junctional adhesion molecule JAM-C regulates polarized transendothelial migration of neutrophils in vivo., in Nature immunology, 12(8), 761-9.
Matricellular protein CCN1/CYR61: a new player in inflammation and leukocyte trafficking
Emre Yalin, Imhof Beat A., Matricellular protein CCN1/CYR61: a new player in inflammation and leukocyte trafficking, in Seminars in Immunopathology, 36, 253-259.

Collaboration

Group / person Country
Types of collaboration
Sussan NOURSHARGH, London Great Britain and Northern Ireland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
Alisa E. KOCH, Ann Arbor United States of America (North America)
- in-depth/constructive exchanges on approaches, methods or results
Stephanie Hugues, Geneva Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
Thomas Matthes Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Exchange of personnel
Ralf ADAMS, Münster Germany (Europe)
- in-depth/constructive exchanges on approaches, methods or results
Kairbaan HODIVALA-DILKE, London Great Britain and Northern Ireland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
Britta ENGELHARDT, Bern Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Urs Christen Germany (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure

Associated projects

Number Title Start Funding scheme
129700 Role of dendritic cell subsets in Leishmania infection 01.05.2010 ProDoc
127182 Infection & Immunity Training 01.09.2009 ProDoc
120184 Junctional adhesion molecules, versatile players in inflammatory immune reactions 01.04.2008 Project funding
153456 Neue matrizelluläre Moleküle beteiligt bei Angiogenese und vaskulären Erkrankungen 01.04.2014 Project funding

Abstract

This is a continuation of our project aiming to understand how the junction adhesion molecules B and C (JAM-B, JAM-C) interfere in inflammatory and immune reactions. The two molecules, previously cloned by our laboratory, are expressed by vascular endothelial cells and they control vascular permeability, cell polarity and leukocyte transmigration.During the last grant period, we investigated molecular interactions of JAM-B and -C by Plasmon resonance technology and gene mutation of potential binding sites. Thereby we found JAM-B/JAM-C interaction of high affinity. However, the trustable techniques did not confirm the described interactions with JAM ligands such as the leukocyte integrin Mac-1. As most lymphocytes/leukocytes do not express JAM-B or -C and interact with vascular JAM-C, searching for novel, unknown ligands is in need. This will be performed by biochemistry and the so-called yeast two-hybrid system using extracellular JAM domains as baits. The suggested experiments should clarify how JAM-C and its novel ligands contribute to the one-way traffic of leukocytes into inflamed tissue and what signal transduction mechanisms prevail. Video microscopy and two photon technology will continue to be used to visualize JAM interactions in vivo.Antibodies against JAMs and soluble recombinant molecules will potentially make valuable tools for treatment of inflammatory pathologies. For testing of JAM-C we used several experimental systems with promising outcome. However, JAM-B testing has just started with one of the models (glomerulonephritis) during our last period. As we found JAM-B expressed in brain endothelium, we wish to learn whether it played a role in multiple sclerosis (MS), since MS triggering lymphocytes express and use integrin alpha 4 for which JAM-B is a ligand. The chosen testing system will be experimental autoimmune encephalomyelitis (EAE) for which our department has ample expertise.Recently we found JAM-C prominently expressed by human T cells after in vitro TCR activation. The functional role of this expression is unknown. Therefore we will investigate the effect of lymphocyte JAM-C in vitro on migration behavior, survival and cytokine secretion of these T-cells. Furthermore we will transfer these cells into immunodeficient NOD/Scid animals in order to study in vivo behavior. The latter experiments have been successfully applied in our laboratory using human B lymphocytes and leukemia cells. Clearly JAM-C expression by a B-cell subpopulation changes its migration behavior (manuscript in preparation).As JAMs are clearly polarity proteins, their expression may affect tissue specific differentiation of embryonic stem cells (ESC). We will use ESC lines, manipulate the expression levels of the JAMs by knock down and over expression technologies and investigate VEGF driven differentiation of these ESCs into polarized endothelial cells. The aim of these experiments will be vascular repair avoiding teratocarcinoma tumor formation and better understanding of the vascular differentiation process.In conclusion: We will largely extend work on JAM-B in addition to JAM-C. Both molecules are involved in essential steps in inflammatory diseases and tissue differentiation and we are looking forward to further clarify the molecular mechanisms.
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