title: Endothelial expression of CXCR7 and the regulation of systemic CXCL12 levels.
abstract: The concentration of CXCL12/SDF-1 in the bloodstream is tightly regulated, given its central role in leucocyte and stem/progenitor cell egress from bone marrow and recruitment to sites of inflammation or injury. The mechanism responsible for this regulation is unknown. Here we show that both genetic deletion and pharmacological inhibition of CXCR7, a high-affinity CXCL12 receptor, caused pronounced increases in plasma CXCL12 levels. The rise in plasma CXCL12 levels was associated with an impairment in the ability of leucocytes to migrate to a local source of CXCL12. Using a set of complementary and highly sensitive techniques, we found that CXCR7 protein is expressed at low levels in multiple organs in both humans and mice. In humans, CXCR7 was detected primarily on venule endothelium and arteriole smooth muscle cells. CXCR7 expression on venule endothelium was also documented in immunodeficient mice and CXCR7(+/lacZ) mice. The vascular expression of CXCR7 therefore gives it immediate access to circulating CXCL12. These studies suggest that endothelial CXCR7 regulates circulating CXCL12 levels and that CXCR7 inhibitors might be used to block CXCL12-mediated cell migration for therapeutic purposes.
authors.affiliation: ChemoCentryx, Inc., Mountain View, CA, USA.
authors.forename: Robert D
authors.initials: RD
authors.lastname: Berahovich
authors.forename: Brian A
authors.initials: BA
authors.lastname: Zabel
authors.forename: Susanna
authors.initials: S
authors.lastname: Lewén
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Walters
authors.forename: Karen
authors.initials: K
authors.lastname: Ebsworth
authors.forename: Yu
authors.initials: Y
authors.lastname: Wang
authors.forename: Juan C
authors.initials: JC
authors.lastname: Jaen
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Schall
mesh_terms: D000818:Animals; D002465:Cell Movement / Q000276:immunology; D054377:Chemokine CXCL12 / Q000097:blood / Q000276:immunology*; D004730:Endothelium, Vascular / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D005786:Gene Expression Regulation / Q000276:immunology*; D061307:Human Umbilical Vein Endothelial Cells / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D007962:Leukocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D051379:Mice; D009928:Organ Specificity / Q000276:immunology; D054387:Receptors, CXCR / Q000096:biosynthesis / Q000276:immunology*
chemical_list: C501896:ACKR3 protein, human; C515255:CXCL12 protein, human; D054377:Chemokine CXCL12; C501897:Cmkor1 protein, mouse; C515256:Cxcl12 protein, mouse; D054387:Receptors, CXCR
keywords: CXCL12; CXCR4; CXCR7; chemotaxis; endothelial