Endothelial expression of CXCR7 and the regulation of systemic CXCL12 levels

Abstract

Summary The concentration of CXCL 12/ 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 CXCR 7, a high‐affinity CXCL 12 receptor, caused pronounced increases in plasma CXCL 12 levels. The rise in plasma CXCL 12 levels was associated with an impairment in the ability of leucocytes to migrate to a local source of CXCL 12. Using a set of complementary and highly sensitive techniques, we found that CXCR 7 protein is expressed at low levels in multiple organs in both humans and mice. In humans, CXCR 7 was detected primarily on venule endothelium and arteriole smooth muscle cells. CXCR 7 expression on venule endothelium was also documented in immunodeficient mice and CXCR 7 +/lacZ mice. The vascular expression of CXCR 7 therefore gives it immediate access to circulating CXCL 12. These studies suggest that endothelial CXCR 7 regulates circulating CXCL 12 levels and that CXCR 7 inhibitors might be used to block CXCL 12‐mediated cell migration for therapeutic purposes.