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 Blood, 4 June 2009, Vol. 113, No. 23, pp. 5801-5810.
Prepublished online as a Blood First Edition Paper on April 3, 2009; DOI 10.1182/blood-2008-08-176123.

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IMMUNOBIOLOGY

Cytohesin-1 controls the activation of RhoA and modulates integrin-dependent adhesion and migration of dendritic cells

Thomas Quast1,*, Barbara Tappertzhofen1,*, Cora Schild1, Jessica Grell1, Niklas Czeloth2, Reinhold Förster2, Ronen Alon3, Line Fraemohs4, Katrin Dreck1, Christian Weber4, Tim Lämmermann5, Michael Sixt5, and Waldemar Kolanus1

1 Life and Medical Sciences (LIMES) Institute, Laboratory for Molecular Immunology, University of Bonn, Bonn, Germany; 2 Institute of Immunology, Hannover Medical School, Hannover, Germany; 3 Department of Immunology, The Weizmann Institute of Science, Rehovot, Israel; 4 Institute for Molecular Cardiovascular Research (IMCAR), Rheinisch-Westfaelische Technische Hochschule (RWTH) University Aachen, Aachen, Germany; and 5 Max-Planck-Institute for Biochemistry, Martinsried, Germany

Adhesion and motility of mammalian leukocytes are essential requirements for innate and adaptive immune defense mechanisms. We show here that the guanine nucleotide exchange factor cytohesin-1, which had previously been demonstrated to be an important component of beta-2 integrin activation in lymphocytes, regulates the activation of the small GTPase RhoA in primary dendritic cells (DCs). Cytohesin-1 and RhoA are both required for the induction of chemokine-dependent conformational changes of the integrin beta-2 subunit of DCs during adhesion under physiological flow conditions. Furthermore, use of RNAi in murine bone marrow DCs (BM-DCs) revealed that interference with cytohesin-1 signaling impairs migration of wild-type dendritic cells in complex 3D environments and in vivo. This phenotype was not observed in the complete absence of integrins. We thus demonstrate an essential role of cytohesin-1/RhoA during ameboid migration in the presence of integrins and further suggest that DCs without integrins switch to a different migration mode.


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