Macrophage CXCR7: A Potential New Target for Atherosclerosis
Type of Degreedissertation
Restriction TypeAuburn University Users
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Objective—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 “decoy” receptor has been in debate. It is known that CXCR7 is not expressed in normal blood leukocytes; however, the potential role of leukocyte CXCR7 in disease states has not been addressed. The aim of this study was to determine the expression and function of macrophage CXCR7 linked to atherosclerosis. Methods and Results— Here we show for the first time that CXCR7 was detected in macrophage-positive area of aortic atheroma of ApoE-null mice, but not in healthy aorta. During monocyte-to-macrophage differentiation, CXCR7 was up-regulated at mRNA and protein levels, with more expression in M1 than in M2 phenotype. In addition, CXCR7 induction was associated with a SDF-1 signaling switch from pro-survival ERK and AKT pathways in monocytes to pro-inflammatory JNK and p38 pathways in macrophages. The latter effect was mimicked by CXCR7-selective agonist TC14012, and abolished by siRNA knockdown of CXCR7. Moreover, CXCR7 activation increased macrophage phagocytic activity, which was suppressed by CXCR7 siRNA silencing or by inhibiting either the JNK or p38 pathways, but was not affected by blocking CXCR4. Activation of CXCR7 by I-TAC showed a similar signaling and phagocytic activity in macrophages with no detectable CXCR3. Our results also suggest that CXCR7 activation potentially prompted macrophage migration and adhesion, and also modulated some candidate genes expression related to atherosclerosis and inflammation. Finally, we found that the induced CXCR7 expression during monocyte-to-macrophage differentiation was diminished by atorvastatin treatment. Conclusions—CXCR7 is induced during monocyte-to-macrophage differentiation, which is required for SDF-1 and I-TAC signaling to JNK and p38 pathways, leading to enhanced macrophage phagocytosis, thus possibly contributing to atherogenesis. In addition, atorvastatin inhibits CXCR7 induction on macrophages, suggesting a new CXCR7-dependent mechanism to benefit atherosclerosis treatment independent of lipid lowering effect.
- Wanshu Ma.pdf