White blood cells (leukocytes) are constantly flowing in the blood stream looking for pathogens which occur, for example, during inflammatory reactions. However, they are only able to reach the most distant corners of our tissue by extravasating and migrating from the blood vessels into the tissue in a complex process known as leukocyte recruitment. The leukocytes use specific adhesion molecules to attach themselves to the vascular wall so that they are not swept away by the flow of blood.

These adhesion molecules seem to have a sweet tooth. In order for the adhesion molecules to function properly, they have to be equipped with a sugar molecule tail, as Dr. David Frommhold from the Neonatal Unit at the Centre for Children's and Youth Medicine at the University of Heidelberg and Dr. Andreas Ludwig from the University of Aachen report in the “Journal of Experimental Medicine.”

Frommhold’s team of scientists, who are specialists in leukocyte recruitment, is working in cooperation with an outstanding international team of researchers led by Professor Dr. Markus Sperandio, who came from the University of Heidelberg to the Walter Brendel Centre for Experimental Medicine at the Ludwig Maximilian University in Heidelberg in 2007. The scientists have now succeeded in showing, in living tissue, that adhesion molecules that enable leukocytes to effectively attach themselves to the vessels of inflamed tissue also need sugar side chains to function properly.

Only recently, the researchers have been able to show in living mice that the adhesion molecules need to be equipped with specific sugar chains so that the leukocytes can make close contact with the endothelium during an inflammatory response. “Sugar chains of various lengths are attached to adhesion molecules during their production. Therefore, the question arose as to whether the sugar chains have a special function for the leukocytes in the living organism,” said Frommhold.

During an inflammatory response, the immune system releases substances known as chemokines that attract the white blood cells flowing in the blood stream. The leukocytes then attach themselves firmly to the endothelial cells of the inflamed tissue. In neutrophil granulocytes, a group of leukocytes that are particularly specialised in bacterial defence, the chemokine interleukin 8 contributes considerably to the granulocytes attaching firmly to the inflamed endothelium. The chemokine receptor, CXCR2, on leukocytes and equipped with specific sugar residues, enables the defence cells to pass through the inflamed tissue. “If the leukocytes’ chemokine receptors are not equipped with specific sugar molecules, then the leukocytes cannot leave the blood stream and the defence against bacteria is severely impeded,” said Frommhold summarising that ‘iced’ leukocytes work a lot better than leukocytes without ‘icing’.

The researchers are convinced that their work will lead to further investigations into the function of sugar molecules in the immune system and open up new strategies for the treatment of acute and chronic inflammatory processes.

Literature:
David Frommhold, Andreas Ludwig, M. Gabriele Bixel, Alexander Zarbock, Inna Babushkina, Melitta Weissinger, Sandra Cauwenberghs, Lesley G. Ellies, Jamey D. Marth, Annette G. Beck-Sickinger, Michael Sixt, Bärbel Lange-Sperandio, Alma Zernecke, Ernst Brandt, Christian Weber, Dietmar Vestweber, Klaus Ley, and Markus Sperandio: "Sialyltransferase ST3Gal-IV controls CXCR2-mediated firm leukocyte arrest during inflammation", Journal of Experimental Medicine, 9 June 2008, B. 205, No. 6, p. 1435-1446
Sperandio M, Frommhold D, Babushkina I, Ellies LG, Olson TS, Smith ML, Fritzsching B, Pauly E, Smith DF, Nobiling R, Linderkamp O, Marth JD, Ley K: ST3Gal-IV is essential for L-selectin ligand function in inflammation. Eur J Immunol 36:3207-3215, 2006

Source: University Hospital Heidelberg - 10 July 2008

Further information:
Dr. David Frommhold
University Hospital Heidelberg
Neonatal Unit
Centre for Children's and Youth Medicine
Tel.: +49 (0)6221-56 39356
E-mail: david.frommhold(at)med.uni-heidelberg.de