Rap1a activation by CalDAG-GEFI and p38 MAPK is involved in E-selectin-dependent slow leukocyte rolling
✍ Scribed by Anika Stadtmann; Laura Brinkhaus; Helena Mueller; Jan Rossaint; Matteo Bolomini-Vittori; Wolfgang Bergmeier; Hugo Van Aken; Denisa D. Wagner; Carlo Laudanna; Klaus Ley; Alexander Zarbock
- Book ID
- 102164326
- Publisher
- John Wiley and Sons
- Year
- 2011
- Tongue
- English
- Weight
- 402 KB
- Volume
- 41
- Category
- Article
- ISSN
- 0014-2980
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✦ Synopsis
Rolling leukocytes are exposed to different adhesion molecules and chemokines. Neutrophils rolling on E-selectin induce integrin a L b 2 -mediated slow rolling on ICAM-1 by activating a phospholipase C (PLC)c2-dependent and a separate PI3Kc-dependent pathway. E-selectinsignaling cooperates with chemokine signaling to recruit neutrophils into inflamed tissues. However, the distal signaling pathway linking PLCc2 (Plcg2) to a L b 2 -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 À/À 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 PLCc2 and Rap1a. Ga i -independent leukocyte adhesion to and transmigration through endothelial cells in inflamed postcapillary venules of the cremaster muscle were completely abolished in Rasgrp2 À/À 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 À/À leukocytes treated with pertussis toxin to block Ga i -signaling. Our data demonstrate that Rap1a activation by p38 MAPK and CalDAG-GEFI is involved in E-selectin-dependent slow rolling and leukocyte recruitment.