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The molecular basis of leukocyte transendothelial migration: from intracellular GEFs to intercellular gaps.

Dr J.D. van Buul

Duration:

Name researcher:

4 years

Amount granted:

€560.000

Year:

2010

Project number:

1028F

Project leader:

Dr Jaap D. van Buul, Dept. of Molecular Cell Biology, Sanquin Research, Amsterdam
PhD student: Niels Heemskerk, Msc (Sept. 2011 – Sept. 2015)
PhD student: Anna E. Daniel, MSc (Sept. 2011 – Sept. 2015)

About the project

Nowadays we know that the blood vessel is much more than a blood transport duct. White blood cells move through the blood vessel wall, and the vessel wall by means of the endothelial cell actively supports in this process. It is all the more remarkable that during this process, that in fact takes place at specific spots about a billion times a day (!), hardly any leakage from the circulation is detected. This is one of the most amazing phenomena of the blood circulation, but also one of the least well understood.
With this project we have clarified the molecular mechanism behind this fascinating phenomenon. This project has increased the fundamental insights of white blood cell transmigration across the vessel wall. Because white blood cell transmigration occurs in many clinical disorders (chronic inflammation, rheumatoid arthritis) but is also essential for the conservation of our daily immune system, understanding this process is essential to specify clinical targets.

In brief, our research showed that the endothelium actively induces F-actin-rich rings around a penetrating leukocyte that function as “elastic straps” sealing the gap and thereby limiting vascular leakage (Heemskerk et al., Nat Comm 2016). We have shown this in in vitro assays but also in relevant inflammatory in vivo experiments. Our work is ground breaking in the field of leukocyte TEM since we show for the first time, using a novel FRET-based biosensor approach, that leukocytes cross the endothelium independent of endothelial cell-contraction. The current dogma states that endothelial cells locally contract to open the cell-cell junctions and thereby allowing leukocytes to cross. Our work shows that endothelial cells that are deficient in cell-contraction and tension allow leukocytes to cross as efficient as in control conditions. Our findings are well accepted and several review papers have already adapted and cited our findings and changed the current view on leukocyte TEM.

Impact of the work: This work was recently cited in a review by Prof. Dr, D. Vestweber in Nat Rev Immunol. 2015 by a personal communication with our lab, stating the above novel findings. This was included in this review since our publication was not officially released a the time of review publication. Another review by William Muller (Curr Opin Hematol 2016) also fully accepted our ideas and changes that our work made to the current dogma in the field of leukocyte TEM.
At present, I am working on an extensive invited review with Prof Alon (Weizman Institute) to be published in Trends in Immunology (IF 11.4). The group of Dr. Alon confirmed our data in their recent publication in Cell Reports.

Next to that, our work was picked up by the daily newspaper De Volkskrant. On January 28th 2016, the Science section reported on our findings including a photograph. Our findings were also reported in the Reformatorisch Dagblad Science section.

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