| First Author | Stadtmann A | Year | 2011 |
| Journal | Eur J Immunol | Volume | 41 |
| Issue | 7 | Pages | 2074-85 |
| PubMed ID | 21480213 | Mgi Jnum | J:177314 |
| Mgi Id | MGI:5294728 | Doi | 10.1002/eji.201041196 |
| Citation | Stadtmann A, et al. (2011) Rap1a activation by CalDAG-GEFI and p38 MAPK is involved in E-selectin-dependent slow leukocyte rolling. Eur J Immunol 41(7):2074-85 |
| abstractText | Rolling leukocytes are exposed to different adhesion molecules and chemokines. Neutrophils rolling on E-selectin induce integrin alphaLbeta2-mediated slow rolling on ICAM-1 by activating a phospholipase C (PLC)gamma2-dependent and a separate PI3Kgamma-dependent pathway. E-selectin-signaling cooperates with chemokine signaling to recruit neutrophils into inflamed tissues. However, the distal signaling pathway linking PLCgamma2 (Plcg2) to alphaLbeta2-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 PLCgamma2 and Rap1a. Galphai-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 Galphai-signaling. Our data demonstrate that Rap1a activation by p38 MAPK and CalDAG-GEFI is involved in E-selectin-dependent slow rolling and leukocyte recruitment. |
