Abstract 77: CXCR7 Induction, Signaling and Phagocytic Function in Macrophages Linked with Atherosclerosis

Abstract

The discovery of CXCR7 as a new receptor for SDF-1 places many previously described SDF-1 functions attributed to CXCR4 in question, though whether CXCR7 acts as a signaling or non-signaling “decoy” receptor has been in debate. A recent study demonstrated that CXCR7 is not expressed in normal human or mouse blood leukocytes; however, the potential role of leukocyte CXCR7 in disease states has not been addressed. Here, we show that CXCR7 was detected in macrophage-positive area of aortic atheroma of ApoE-null mice, but not in healthy arteries. Consistent with this, we found that during monocyte-to-macrophage differentiation, CXCR7 was dramatically upregulated at both mRNA and protein levels. In addition, CXCR7 induction was associated with a SDF-1 signaling switch from pro-survival to pro-inflammatory pathways including p38 and JNK, which was mimicked by a CXCR7-selective agonist and inhibited by CXCR7-blocking antibodies, but not by CXCR4-selective antagonist. Furthermore, we found that CXCR7 activation by SDF-1 or its selective agonist TC14012 significantly increased macrophage phagocytosis, which was suppressed by inhibiting either the p38 or JNK pathways. We conclude that CXCR7 is induced during monocyte-to-macrophage differentiation, which mediates signaling to p38 and JNK pathways, leading to enhanced cellular phagocytic function, thus possibly contributing to atherogenesis.