Dr. Alexander Zarbock1,2in cooperation with PD Dr. Martin Wild1Westphalian Wilhelm's University of Münster 1Max-Planck Institute for Molecular Biomedicine Department of Vascular Cell Biology Röntgenstrasse 20 48149 Münster 2Department of Anesthesiology and Critical Care Medicine Albert-Schweitzer-Str. 33 48149 Münster |  |
| Email: Net: | zarbock@uni-muenster.de www.mpi-muenster.mpg.de/nvz/vz.shtml |
The research group of Dr. Alexander Zarbock is interested in understanding the molecular mechanisms of leukocyte recruitment into inflamed tissue. Glycosylation of adhesion molecules participating in leukocyte recruitment is of particular importance.
Leukocyte recruitment into inflamed tissue is tightly regulated. Reduced neutrophil recruitment can result in a diminished ability to fight invading microorganisms. During inflammation, leukocytes roll along the endothelial wall and integrate inflammatory signals. Leukocyte activation by carbohydrate-binding selectins and by chemokines regulates integrin adhesiveness. Binding of activated integrins to their counter-receptors on endothelial cells induces leukocyte arrest and firm adhesion. Adherent neutrophils can be further activated to undergo crawling, transmigration and respiratory burst.
 | Intravital microscopy of the cremaster muscle of mixed chimeric mice 6 weeks after bone marrow transplantation. Neutrophils from LysM-GFP+ mice (black circle) and gene-deficient mice (GFP- cells, white circle). |
The first step of this cascade (‘capturing’) is mediated by selectins expressed on endothelial cells and the main counter-receptor, P-selectin glycoprotein ligand (PSGL)-1, on leukocytes. PSGL-1 can bind all selectins (P-, E-, and L-selectin). For optimal selectin binding, PSGL-1 must undergo post-translational modifications. Several glycosyltransferases are involved in this process including core 2 N-acetylglucosaminyltransferase, α1-3 fucosyltransferases FucT-VII and FucT-IV, β1-4 galactosyltransferase-1, and α2-3 sialyltransferase ST3GalIV. Studies with mice lacking one or multiple of these glycosyltransferases demonstrated a broad array of leukocyte rolling defects ranging from a mild capturing defect to an almost complete loss of leukocyte rolling. In addition to these modifications, sulfation of tyrosines near the N-terminus of PSGL-1 by distinct tyrosylsulfotransferases contributes to the enhanced P-selectin binding to PSGL-1. Binding of selectins to their counter-receptors not only mediates capturing but also activates different signaling pathways. Understanding the different signaling pathways and how they interact may facilitate the development of therapeutics that only modulate the desired function.
Our work is supported by a strong interdisciplinary and international network.
