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- Title
Dual signaling pathways control LFA-1 mediated rolling and arrest on ICAM-1.
- Authors
Zarbock, Alexander; Ley, Klaus
- Abstract
Leukocyte recruitment into site of inflammation proceeds in a multistep cascade involving selectin-mediated rolling, chemokine-triggered activation and integrin-mediated adhesion. Leukocyte integrins also support slow rolling upon selectin tethering. The signaling pathways downstream of E-selectin binding are largely unknown. Intravital microscopy of the murine cremaster muscle and a blood perfused flow chamber system were used to determine that P-selectin glycoprotein ligand (PSGL)-1, but not CD44, induced slow rolling on a surface coated with E-selectin and ICAM-1. Slow rolling was entirely dependent on CD11a (LFA-1), but not CD11b (Mac-1). The E-selectin-induced signal was required to keep integrins in an activated conformation; there was no apparent "memory" for prior engagement of E-selectin ligands. Slow roiling mediated by LFA-1 was abolished by blocking spleen tyrosine kinases (Syk) using the inhibitor Piceatannol. The pretreatment of the mice with tumor necrosis factor (TNF)-α induced leukocyte adhesion in chambers coated with E-selectin and ICAM-1 alone. This adhesion was caused by KC produced by neutrophils in response to TNF-α treatment which acted in an autocrine/paracrine manner and was completely abolished by blocking CXCR2. We conclude that PSGL-1 is the E-selectin ligand which signals and induces slow rolling by Syk-dependent integrin activation. This signaling is neither required nor sufficient for integrin-mediated arrest, which is CXCR2-dependent.
- Subjects
LEUCOCYTE motility; SELECTINS; CHEMOKINES; INTEGRINS; BLOOD flow; GLYCOPROTEINS; LIGANDS (Biochemistry); PROTEIN-tyrosine kinases
- Publication
FASEB Journal, 2007, Vol 21, Issue 6, pA849
- ISSN
0892-6638
- Publication type
Article
- DOI
10.1096/fasebj.21.6.a849-b