title: Induction of C-X-C chemokine receptor type 7 (CXCR7) switches stromal cell-derived factor-1 (SDF-1) signaling and phagocytic activity in macrophages linked to 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 "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. Here, we show that CXCR7 was detected in macrophage-positive area of aortic atheroma of ApoE-null mice, but not in healthy aorta. During monocyte differentiation to macrophages, 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 the pro-survival ERK and AKT pathways in monocytes to the pro-inflammatory JNK and p38 pathways in macrophages. The latter effect was mimicked by a CXCR7-selective agonist TC14012 and abolished by siRNA knockdown of CXCR7. Furthermore, 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. Finally, activation of CXCR7 by I-TAC showed a similar signaling and phagocytic activity in macrophages with no detectable CXCR3. We conclude that 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.
authors.affiliation: Division of Pharmacology, Department of Pharmacal Sciences, Harrison School of Pharmacy, Auburn University, Auburn, Alabama 36849, USA.
authors.forename: Wanshu
authors.initials: W
authors.lastname: Ma
authors.forename: Yiwei
authors.initials: Y
authors.lastname: Liu
authors.forename: Nicholas
authors.initials: N
authors.lastname: Ellison
authors.forename: Jianzhong
authors.initials: J
authors.lastname: Shen
mesh_terms: D000818:Animals; D001011:Aorta / Q000378:metabolism / Q000473:pathology; D050197:Atherosclerosis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D054371:Chemokine CXCL11 / Q000235:genetics / Q000378:metabolism; D054377:Chemokine CXCL12 / Q000235:genetics / Q000378:metabolism*; D005260:Female; D055785:Gene Knockdown Techniques; D006801:Humans; D048670:MAP Kinase Kinase 4 / Q000235:genetics / Q000378:metabolism; D020935:MAP Kinase Signaling System; D008264:Macrophages / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D009000:Monocytes / Q000378:metabolism / Q000473:pathology; D009842:Oligopeptides / Q000494:pharmacology; D010587:Phagocytosis; D058226:Plaque, Atherosclerotic / Q000378:metabolism / Q000401:mortality; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D054387:Receptors, CXCR / Q000235:genetics / Q000378:metabolism*; D054367:Receptors, CXCR3 / Q000235:genetics / Q000378:metabolism; D019718:Receptors, CXCR4 / Q000235:genetics / Q000378:metabolism
chemical_list: C501896:ACKR3 protein, human; C515202:CXCL11 protein, human; C515255:CXCL12 protein, human; C515187:CXCR3 protein, human; C527276:CXCR4 protein, human; C514936:CXCR4 protein, mouse; D054371:Chemokine CXCL11; D054377:Chemokine CXCL12; C501897:Cmkor1 protein, mouse; C515203:Cxcl11 protein, mouse; C515256:Cxcl12 protein, mouse; C515188:Cxcr3 protein, mouse; D009842:Oligopeptides; D054387:Receptors, CXCR; D054367:Receptors, CXCR3; D019718:Receptors, CXCR4; C504129:TC14012; D051057:Proto-Oncogene Proteins c-akt; D048670:MAP Kinase Kinase 4
keywords: Cardiovascular Disease; Chemokines; MAP Kinases (MAPKs); Macrophages; Receptor Regulation