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- Title
Rap1a activation by CalDAG-GEFI and p38 MAPK is involved in E-selectin-dependent slow leukocyte rolling.
- Authors
Stadtmann, Anika; Brinkhaus, Laura; Mueller, Helena; Rossaint, Jan; Bolomini-Vittori, Matteo; Bergmeier, Wolfgang; Van Aken, Hugo; Wagner, Denisa D.; Laudanna, Carlo; Ley, Klaus; Zarbock, Alexander
- Abstract
Rolling leukocytes are exposed to different adhesion molecules and chemokines. Neutrophils rolling on E-selectin induce integrin αβ-mediated slow rolling on ICAM-1 by activating a phospholipase C (PLC)γ2-dependent and a separate PI3Kγ-dependent pathway. E-selectin-signaling cooperates with chemokine signaling to recruit neutrophils into inflamed tissues. However, the distal signaling pathway linking PLCγ2 ( Plcg2) to αβ-activation is unknown. To identify this pathway, we used different Tat-fusion-mutants and gene-deficient mice in intravital microscopy, autoperfused flow chamber, peritonitis, and biochemical studies. We found that the small GTPase Rap1 is activated following E-selectin engagement and that blocking Rap1a in Pik3cg mice by a dominant-negative Tat-fusion mutant completely abolished E-selectin-mediated slow rolling. We identified CalDAG-GEFI ( Rasgrp2) and p38 MAPK as key signaling intermediates between PLCγ2 and Rap1a. Gα-independent leukocyte adhesion to and transmigration through endothelial cells in inflamed postcapillary venules of the cremaster muscle were completely abolished in Rasgrp2 mice. The physiological importance of CalDAG-GEFI in E-selectin-dependent integrin activation is shown by complete inhibition of neutrophil recruitment into the inflamed peritoneal cavity of Rasgrp2 leukocytes treated with pertussis toxin to block Gα-signaling. Our data demonstrate that Rap1a activation by p38 MAPK and CalDAG-GEFI is involved in E-selectin-dependent slow rolling and leukocyte recruitment.
- Publication
European Journal of Immunology, 2011, Vol 41, Issue 7, p2074
- ISSN
0014-2980
- Publication type
Article
- DOI
10.1002/eji.201041196