title: SPARC is a VCAM-1 counter-ligand that mediates leukocyte transmigration.
abstract: VCAM-1 is a cell surface molecule, which has been shown to mediate leukocyte adhesion to the endothelium and subsequent transmigration. Although VCAM-1 regulates adhesion through its interaction with VLA-4, VLA-4 does not play a role in VCAM-1-dependent diapedesis, an observation suggesting the presence of a second ligand for VCAM-1. We now report a novel interaction between VCAM-1 and secreted protein acidic and rich in cysteine (SPARC), which induces actin cytoskeletal rearrangement and intercellular gaps, physiological processes known to be important for leukocyte transmigration. The binding of leukocyte-derived SPARC to VCAM-1 was demonstrated to be necessary for leukocyte transmigration through endothelial monolayers (diapedesis) in vitro, and furthermore, SPARC null mice have abnormalities in leukocyte recruitment to the inflamed peritoneum in vivo. These findings provide new insight into the mechanisms of transendothelial leukocyte migration and suggest a potential, targetable interaction for therapeutic intervention.
authors.affiliation: Harvard Medical School, Massachusetts General Hospital, Charlestown, MA 02129, USA. kkelly9@partners.org
authors.forename: Kimberly A
authors.initials: KA
authors.lastname: Kelly
authors.forename: Jennifer R
authors.initials: JR
authors.lastname: Allport
authors.forename: Amy M
authors.initials: AM
authors.lastname: Yu
authors.forename: Sumita
authors.initials: S
authors.lastname: Sinh
authors.forename: E Helene
authors.initials: EH
authors.lastname: Sage
authors.forename: Robert E
authors.initials: RE
authors.lastname: Gerszten
authors.forename: Ralph
authors.initials: R
authors.lastname: Weissleder
mesh_terms: D000199:Actins / Q000502:physiology; D000818:Animals; D002465:Cell Movement / Q000235:genetics / Q000502:physiology; D003599:Cytoskeleton / Q000502:physiology; D005260:Female; D006801:Humans; D007365:Intercellular Junctions / Q000502:physiology; D007962:Leukocytes / Q000502:physiology*; D008024:Ligands; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D015676:Osteonectin / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D013329:Structure-Activity Relationship; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism*
chemical_list: D000199:Actins; D008024:Ligands; D015676:Osteonectin; D019010:Vascular Cell Adhesion Molecule-1