​CELL BIOLOGY OF INFLAMMATION

Crossregulation between leukocyte transendothelial migration and endothelial permeability

 

TNF is the paradigm of cytokine that exert long-term proinflammatory stimulation. TNF alters endothelial barrier function by remodelling endothelial cell-cell junctions. We are investigating the contribution to the integrity of cell-cell junctions of the actin cytoskeleton and the adhesion receptors involved in leukocyte transendothelial migration. We described the strategy leukocytes pursue to transmigrate without altering endothelial permeability, away from cell-cell junctions, which has been called transcellular diapedesis. Alternatively, adhesion receptors involved in paracellular leukocyte diapedesis, such as PECAM-1, may play a double role by modulating cell-cell junction upon engagement by leukocytes. In a context of low inflammatory response, in which the permeability of the endothelium is reduced, PECAM-1 may mediate the local disruption of cell-cell junctions to facilitate leukocyte passage. In collaboration with Drs. Susan Cox and Anne J. Ridley, at Kings College of London, we have reported for the first time an analysis of endothelial cell-cell contacts by super-resolution confocal microscopy. We have described a unique supramolecular organization of VE-cadherin-mediated junctional complexes that are stabilized by the adhesion receptor PECAM-1 in the absence of filamentous actin. We have called this reticular junctions (see top Figure).

Upon TNF stimulation, reticular junctions are disrupted and PECAM-1 is dispersed. Concomitantly, junctional F-actin increases and Adherens Junctions, formed by VE-cadherin, appear associated to actin stress fibers. Interestingly, Adherens Junctions stabilize these fibers independently of focal adhesions in inflamed endothelial monolayers.

 

 

Related Bibliography:

 

1- Marcos-Ramiro B, García-Weber D, Millán J. TNF-induced endothelial barrier disruption: beyond actin and Rho.

Thrombosis and Haemostasis; 2014, http://dx.doi.org/10.1160/TH14A04A0299.

2- Marcos-Ramiro B, Oliva-Nacarino, P., Serrano-Pertierra, E., Blanco-Gelaz, M.A., Weksler,  B.B., Romero I.A., Couraud, P.O., Tuñon, A., Lopez-Larrea, C., Millán, J., and Cernuda, E. Microparticles in multiple sclerosis and clinically isolated syndrome: effect on endothelial barrier function.

BMC Neuroscience; 2014, doi:10.1186/1471-2202-15-110.

 

3- Aranda J.F., Reglero-Real N., Marcos-Ramiro B. Ruiz-Sáenz A., Fernández-Martín L., Bernabé-Rubio M., Kremer L., Ivetic A., Ridley A.J., Correas I., Alonso M.A. and Millán, J. MYADM controls endothelial barrier function through ERM-dependent regulation of ICAM-1
expression.

Molecular Biology of the Cell; 2013, Feb;24(4):483-94.

 

3- Fernández-Martín, L. Marcos-Ramiro, B., Bigarella, CL. Graupera,  M. Cain, RJ.  Reglero-Real, N., Jiménez A, Cernuda-Morollón, E., Correas, I. Cox, S., Ridley, AJ and Millán J.

Crosstalk between Reticular Adherens Junctions and PECAM-1 Regulates Endothelial Barrier Function.

Arterioscler Thromb Vasc Biol. 2012. 32(8):e90-e102.          

 

Reglero-Real, N., Marcos-Ramiro, B. and Millán J. 

Endothelial membrane reorganization during leukocyte extravasation. 

Cell Molecular Life Sciences. 2012.   10.1007/s00018-012-0987-4.   

 

Cernuda-Morollón, E, Gharbi, S. and Millán, J.

Discriminating between the paracellular and transcellular routes of transmigration. “Studying T cell trafficking”.

Methods in Molecular Biology.2010; 616:69-82

 

Millán J (Corresponding author), Cain, R. Reglero-Real, N, Bigarella, C. Marcos-Ramiro, B, Fernández-Martín, L. Correas I. and Ridley A.J.

 Adherens junctions connect stress fibers between adjacent endothelial cells.

BMC Biology. 2010. 8:11.

 

Millán J., Hewlett L., Glyn, M, Toomre, D., Clark, P. and Ridley A.J.

Lymphocyte transcellular migration occurs through recruitment of endothelial ICAM-1 to caveola and F-actin -rich domains.

Nature Cell Biology. 2006. 8, 113-123.

 

Millán J., Williams, L. and Ridley A.J.

An in vitro model to study the role of endothelial Rho GTPases during leukocyte transendothelial migration

Methods in Enzymology. 2006. 406, 643-55                                              

 

Millán, J and Ridley, A.J.

Rho GTPases and leucocyte-induced endothelial remodelling.

Biochemical Journal. 2005. 385:329-337