Journal
EUROPEAN JOURNAL OF IMMUNOLOGY
Volume 41, Issue 7, Pages 2074-2085Publisher
WILEY-BLACKWELL
DOI: 10.1002/eji.201041196
Keywords
CalDAG-GEFI; Integrin; p38; Rap1a; Signaling
Categories
Funding
- German Research Foundation [AZ 428/3-1]
- Interdisciplinary Clinical Research Center (IZKF Muenster, Germany) [Za2/001/10]
- NIH [NHLBI POI HL056949]
- American Heart Association
- Fondazione Cariverona, Verona, Italy
- Associazione Ricerca sul Cancro (AIRC), Italy
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Rolling leukocytes are exposed to different adhesion molecules and chemokines. Neutrophils rolling on E-selectin induce integrin alpha(L)beta(2)-mediated slow rolling on ICAM-1 by activating a phospholipase C (PLC)gamma(2)-dependent and a separate PI3K gamma-dependent pathway. E-selectin-signaling cooperates with chemokine signaling to recruit neutrophils into inflamed tissues. However, the distal signaling pathway linking PLC gamma 2 (Plcg2) to alpha(L)beta(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(-/-) 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 PLC gamma 2 and Rap1a. G alpha(i)-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 G alpha(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.
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