​CELL BIOLOGY OF INFLAMMATION
RESEARCH OVERVIEW
Inflammation is a primary response to infection, stress and injury in the innate immune defense. 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 paradigmatic cytokine for studying the molecular mechanisms underlying the alteration of cellular barriers during the inflammatory response.
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.
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.
Human vascular endothelial cells (HUVECs) stained for the cell-cell junction marker beta-catenin (green) and actin (red)
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 traverse first the endothelial barriers and then interact with parenchymal cell barriers. The latter often contain dysfunctional, damaged or highly inflamed cells that constitute the the final destination of migrating leukocytes.