Controlling the entry of leukocytes into tissue

Leukocyte extravasation is usually triggered by pathological stimuli such as physical injury or infectious microorganisms and is the starting event that initiates the process of inflammation and that controls its continuation. Understanding its molecular basis will allow to interfere with and modulate the often harmful consequences of the inflammatory process.

Leukocyte capturing and adhesion: The entry of leukocytes into tissue is controlled by molecular factors that activate the endothelium and the leukocytes and by adhesion molecules that mediate the contact between both cell types. Selectins, a small family of three adhesion molecules (L-, E- and P-selectin) that bind to carbohydrates initiate leukocyte capturing to endothelial cells, which enables leukocytes to sense chemotactic factors such as chemokines on the surface of the endothelium. This leads to the activation of leukocyte integrins that mediate firm adhesion to the blood vessel wall and migration of leukocytes towards a source of chemotactic factors. Following this selectin-, chemokine-, integrin-driven cascade of molecular interactions, leukocytes finally transmigrate through the blood vessel wall by mechanisms that are not yet well understood.

Our group contributed to the identification and analysis of selectin ligands. In addition we clarified the molecular basis of the human genetic disease called leukocyte adhesion deficiency II (LAD-II), a general defect in the biosynthesis of the carbohydrate ligands of selectins. Together with clinicians at our University in Münster we could establish the first successful therapy (a fucose substitution therapy) that cured the immunodeficiency defect in LADII patients.

Leukocyte diapedesis: Since a few years a major part of our activities is now directed towards tackling the question, how leukocytes actually move through and overcome the blood vessel barrier - a process called diapedesis. We are analyzing this process in vitro and in vivo. The latter is based on generating gene deficient and conditional gene deficient mice and analyzing leukocyte extravasation direcly by intravital microscopy. We identified and analyzed several membrane proteins at endothelial cell contacts that support leukocyte diapedesis such as the endothelial tight junction associated protein ESAM, and the two related small membrane proteins CD99 and CD99L2. In addition we are actively analyzing how leukocytes open endothelial cell contacts. We believe that an endothelial specific receptor type protein tyrosine phosphatase (VE-PTP) represents an essential switch that controls the activity of VE-cadherin and thereby the integrity of endothelial junctions during leukocyte diapedesis.

The role of endothelial cell contacts in angiogenesis

We are investigating how the formation of endothelial cell contacts and the plasticity of endothelial junctions regulate angiogenesis during embryonic development and tumor growth. Also in this context we focus on the endothelial phosphatase VE-PTP. This phosphatase is of major importance for the regulation of the adhesive function of VE-cadherin and for balancing the activity of the tyrosine kinase receptor Tie-2. VE-cadherin and Tie-2 are both essential players in angiogenesis. In addition to angiogenesis, the interplay of these three proteins also regulates the stability of endothelial cell contacts and thereby the integrity of the vascular barrier in adult organisms. The molecular basis for this is presently under investigation.

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