Wednesday, 29th January 2020

Cell biology of inflammation


2016 02 Grupo Jaime Millan 400px


Jaime Millán








Research summary:

Inflammation is a primary response to infection, stress and injury. Pathological and chronic inflammation leads to diseases such as atherosclerosis, multiple sclerosis or hepatitis. Long-term inflammatory responses are orchestrated by the secretion of soluble factors that stimulate cells in the surroundings of an inflammatory focus. Among these, the pro inflammatory cytokine TNF is central to inflammation and facilitates the recruitment of immune cells to damaged tissue areas by disrupting cellular barriers. We use TNF as a model cytokine for studying the molecular mechanisms underlying the alteration of cellular barriers during the inflammatory response.


Reticular endothelial cell-cell junctions composed of PECAM-1 (red), an adhesion receptor involved in leukocyte diapedesis, and VE-cadherin (green).
 endocornea pequeno
The Endocornea project is a collaboration between the Instituto de Investigación Sanitaria Fundación Jiménez Díaz and CSIC to investigate the molecular mechanisms regulating corneal endothelial barrier function and its responses to inflammatory stress.


Our research interest: Cellular barriers in the lymphocyte journey through the inflamed tissue. Inflammatory cytokines, such as TNF, modulate the integrity of cellular barriers to facilitate the passage of solutes and immune cells from the bloodstream to the inflammatory focus in the tissue. Leukocytes first traverse endothelial barriers and then interact with parenchymal cell barriers. The latter often contain dysfunctional, damaged or highly inflamed cells that constitute the final destination of migrating leukocytes. In the liver parenchyma, leukocyte infiltration is essential to control cancer, infections and hepatic inflammatory diseases.


Endothelial cells line the inner surface of the vascular wall, where they form a selective barrier that controls the passage of cells and solutes between the blood and the parenchyma in the inflamed tissue. Our group is interested in investigating the effect of TNF on endothelial barrier disruption, using human primary endothelial cells as our main experimental model. First, we are studying the effect of this cytokine on the association of filamentous actin to cell-cell junctions. We are analyzing how TNF alters the localization and expression of receptors involved in leukocyte transendothelial migration, namely PECAM-1 and ICAM-1, which also regulate endothelial permeability. In addition, by combining proteomics, quantitative PCR and immunodetection we have identified a new set of proteins whose expression is regulated in response to TNF. We are currently analyzing the role of some of these proteins in TNF-induced endothelial barrier disruption, with the long-term aim of finding new targets to control the dysfunctional increase of vascular leakiness, which contributes to the development of  pro inflammatory diseases.

In addition, thanks to the support of the Instituto de Investigación Sanitaria Fundación Jiménez Díaz, we are currently investigating the effect of various inflammatory mediators on corneal endothelial barrier function, with the ultimate aim of preventing corneal opacity in eye inflammatory diseases.

Once leukocytes traverse the endothelial barrier in an organ, they establish adhesions with parenchymal cells, searching for the inflammatory focus and for dysfunctional cells. The liver is a paradigm of organ in which leukocyte infiltration into the parenchyma is essential for immune-surveillance, control of cancer and infections and tissue regeneration. We are currently studying the effect of TNF on human hepatic cell barriers and how these barriers control leukocyte trafficking in the parenchyma during inflammation.

Recent publications (2012-2016):


- Ortega MC, Santander-García D, Marcos-Ramiro, B, Barroso S, Cox S, Jiménez-Alfaro I and Millán J. Activation of Rac1 and RhoA preserve corneal endothelial barrier function. Investigative Ophthalmology & Visual Science November 2016, Vol.57, 6210-6222. doi:10.1167/iovs.16-20031

- Santander-García D, Ortega MC, Benito-Martínez S, Barroso S, Jiménez-Alfaro I and Millán J. A human cellular system for analyzing signaling during corneal endothelial barrier dysfunction. Experimental Eye Research. October 2016.

- García-Weber D and Millán, J. Parallels between single cell migration and barrier formation: the case of RhoB and Rac1 trafficking. Small GTPases; 2016,

- Marcos-Ramiro B, García-Weber D, Barroso S, Feito, J, Ortega MC, Cernuda-Morollón, E, Reglero-Real N, Fernández-Martín L, Alonso MA, Correas I, Ridley AJ and Millán J. RhoB controls endothelial barrier recovery by inhibiting Rac1 trafficking to the cell border. Journal of Cell Biology; 2016, 213(3):385-402.

- Reglero-Real R, García-Weber D and Millán J. Cellular Barriers after Extravasation: Leukocyte Interactions with Polarized Epithelia in the Inflamed Tissue. Mediators of Inflammation; 2016,


- Bernabé-Rubio M, Andrés G, Casares-Arias J, Fernández-Barrera J, Rangel L, Reglero-Real N, Gershlick DC, Fernández JJ, Millán J, Correas I, Miguez DG, Alonso MA. New role of the midbody in primary ciliogenesis by polarized epithelial cells. Journal of Cell Biology; 2016, 214(3):259-273.


- Rodríguez-Fraticelli AE, Bagwell J, Bosch-Fortea M, Boncompain G, Reglero-Real N, García-León MJ, Andrés G, Toribio ML, Alonso MA, Millán J, Perez F, Bagnat M, Martín-Belmonte F.Developmental regulation of apical endocytosis controls epithelial patterning in vertebrate tubular organs. Nature Cell Biology, 2015 Mar;17(3):241-50


- Marcos-Ramiro B, García-Weber D, Millán J. TNF-induced endothelial barrier disruption: beyond actin and Rho. Thrombosis and Haemostasis; 2014, 112(6):1088-10.

- 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. (c.a), and Cernuda, E. (c.a) Microparticles in multiple sclerosis and clinically isolated syndrome: effect on endothelial barrier function. BMC Neuroscience; 2014, 12: 110. doi:10.1186/1471-2202-15-110.

- Reglero-Real R, Álvarez-Varela A, Cernuda-Morollón E, Feito J, Marcos-Ramiro B, Fernández-Martín L, Gómez-Lechón MJ, Muntané J, Sandoval P, Majano PL, Correas I, Alonso MA and Millán J. Apicobasal polarity controls lymphocyte adhesion to hepatic epithelial cells. Cell Reports; 2014 ;8(6):1879-93.

- Aranda J.F., Reglero-Real N., Marcos-Ramiro B. Ruiz-Sáenz A., Fernández-Martín L., Bernabé-Rubio M., Kremer L., 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.

- Ruiz-Saenz A, van Haren J, Sayas CL, Rangel L, Demmers J, Millán J, Alonso MA, Galjart N, Correas I. Protein 4.1R binds to CLASP2 and regulates dynamics, organization and attachment of microtubules to the cell cortex. Journal of Cell Science. 2013 Oct 15;126(Pt 20):4589-601

- 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. Arteriosclerosis Thrombosis Vascular Biology. 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. Sep;69(18):3079-99.


Doctoral Theses:

- Natalia Reglero Real (2013). Función de la polaridad apicobasal de las células hepáticas en la adhesion linfocitaria. Implicaciones en la respuesta inflamatoria del hígado.

- Beatriz Marcos Ramiro (2015). La GTPasa endosomal RhoB regula la recuperación de la barrera endotelial durante la inflamación.

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