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

Ma, Wanshu; Liu, Yiwei; Ellison, Nicholas; Shen, Jianzhong

doi:10.1074/jbc.m112.445510

Cited by 66 publications

(81 citation statements)

References 36 publications

(32 reference statements)

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“…Our findings from PLAs and FACS analyses are consistent with the absence of cell surface CXCR7 in THP-1 cells which have not been differentiated into a macrophage-like phenotype [11]. This suggests that monocytic THP-1 cells are a suitable cell system to study the interaction of SDF-1α and ubiquitin on CXCR4, in which possible confounding effects of CXCR7, such as scavenging of SDF-1α or CXCR4-CXCR7 heterodimer formation, are unlikely.…”

Section: Discussionsupporting

confidence: 84%

CXC chemokine receptor 4 signaling upon co-activation with stromal cell-derived factor-1α and ubiquitin

et al. 2014

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Recently, we reported that extracellular ubiquitin functions as another agonist of CXC chemokine receptor (CXCR)4. Whereas the cognate CXCR4 ligand, stromal cell-derived factor (SDF)-1α, is also a CXCR7 agonist, ubiquitin does not bind to CXCR7. Because both ligands are present in the extracellular environment, co-activation of CXCR4 appears to be physiologically relevant. CXCR4 mediated effects of ubiquitin, however, are not well understood and consequences of co-activation of CXCR4 with both ligands are unknown. Utilizing proximity ligation assays and flow cytometry, we detected CXCR4, but not CXCR7, on the cell surface of THP-1 cells, which suggests that confounding effects of CXCR7 are unlikely. Time course and magnitude of reduction of cell surface CXCR4 expression were comparable after stimulation of THP-1 cells with both ligands. SDF-1α was more efficacious than ubiquitin to mobilize Ca2+. Co-stimulation of THP-1 cells with both ligands resulted in synergistic effects on Ca2+ fluxes at suboptimal ligand concentrations. Homologous desensitization of Ca2+ fluxes was detectable with both ligands. SDF-1α pre-stimulation desensitized ubiquitin induced Ca2+ fluxes, but not vice versa. Effects of SDF-1α and ubiquitin on cAMP levels, Akt and ERK1/2 phosphorylation and chemotactic responses were additive. The chemotactic activities of ubiquitin and SDF-1α were sensitive to AMD3100, pertussis toxin, U73122, LY94002 and U0126. These data suggest that CXCR4 activation with SDF-1α and ubiquitin results in partially synergistic effects on cellular signaling events and in differential effects on receptor desensitization. The ligand ratio that is present in the extracellular environment may contribute to the regulation of CXCR4 mediated functions.

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Section: Discussionsupporting

confidence: 84%

CXC chemokine receptor 4 signaling upon co-activation with stromal cell-derived factor-1α and ubiquitin

et al. 2014

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“…28 However, it is unlikely that CXCR7 directly compensates for such effects, because it is not expressed on BM cells. Although CXCR7 expression has been reported previously in lesional macrophages, 29 we did not detect CXCR7 in injured arteries, and genetic deletion of Cxcr7 in BM cells had no effect on neointima formation, which indicates a minor role of CXCR7 in macrophages during vascular repair.…”

Section: Discussioncontrasting

confidence: 47%

Activation of CXCR7 Limits Atherosclerosis and Improves Hyperlipidemia by Increasing Cholesterol Uptake in Adipose Tissue

Zhu

Penfold

et al. 2014

Circulation

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C hemokines, acting through various mechanisms including the recruitment of immune cells and smooth muscle progenitor cells (SPCs) to the vessel wall, 1,2 are crucial for vascular remodeling and atherosclerosis. In addition, chemokines are critical for monocyte and neutrophil homeostasis. Hyperlipidemia-induced monocytosis results from the combined action of various chemokine receptors, such as CCR2, which are expressed by immune cells (including monocytes), and facilitates atherosclerosis.3-5 By contrast, the CXCL12 receptor, CXCR4, protects against atherosclerosis by controlling the mobilization of neutrophils, 6 whereas the mobilization and recruitment of SPCs by CXCL12 during vascular repair aggravates neointima formation, which indicates a contextspecific role for this chemokine-receptor axis in arterial remodeling.7,8 Accordingly, increased levels of CXCL12 and SPCs are observed in patients with severe cardiac allograft vasculopathy.9 Systemic treatment with CXCL12 induces the release of SPCs, which accumulate in atherosclerotic lesions and thus lead to plaque stabilization. 10 Whereas most of the effects of CXCL12 are linked to its interaction with CXCR4, the function of the alternative CXCL12 receptor, CXCR7, in atherogenesis and vascular remodeling is unclear. Clinical Perspective on p 1253Background-The aim of this study was to determine the role of the chemokine receptor CXCR7 in atherosclerosis and vascular remodeling. CXCR7 is the alternative receptor of CXCL12, which regulates stem cell-mediated vascular repair and limits atherosclerosis via its receptor, CXCR4. Methods and Results-Wire-induced injury of the carotid artery was performed in mice with a ubiquitous, conditional deletion of CXCR7 and in mice treated with the synthetic CXCR7 ligand CCX771. The effect of CCX771 treatment on atherosclerosis was studied in apolipoprotein E-deficient (Apoe) mice fed a high-fat diet for 12 weeks. Lipoprotein fractions were quantified in the plasma of Apoe −/− mice by fast protein liquid chromatography. Uptake of DiI-labeled very low-density lipoprotein to adipose tissue was determined by 2-photon microscopy. We show that genetic deficiency of Cxcr7 increased neointima formation and lesional macrophage accumulation in hyperlipidemic mice after vascular injury. This was related to increased serum cholesterol levels and subsequent hyperlipidemia-induced monocytosis. Conversely, administration of the CXCR7 ligand CCX771 to Apoe −/− mice inhibited lesion formation and ameliorated hyperlipidemia after vascular injury and during atherosclerosis. Treatment with CCX771 reduced circulating very lowdensity lipoprotein levels but not low-density lipoprotein or high-density lipoprotein levels and increased uptake of very low-density lipoprotein into Cxcr7-expressing white adipose tissue. This effect of CCX771 was associated with an enhanced lipase activity and reduced expression of Angptl4 in adipose tissue. Conclusions-CXCR7 regulates blood cholesterol by promoting its uptake in adipose tissue. This unexpected choleste...

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“…CD68 is a marker of both monocytes and macrophage but is generally found to be increased after macrophage differentiation by PMA 44,45 . After 16 hr treatment of the THP-1 cells with PMA, CD68 was found to be upregulated (Fig.…”

Section: Resultsmentioning

confidence: 99%

Controlled release of cytokines using silk-biomaterials for macrophage polarization

et al. 2015

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Polarization of macrophages into an inflammatory (M1) or anti-inflammatory (M2) phenotype is important for clearing pathogens and wound repair, however chronic activation of either type of macrophages has been implicated in several diseases. Methods to locally control the polarization of macrophages is of great interest for biomedical implants and tissue engineering. To that end, silk protein was used to form biopolymer films that release either IFN-γ or IL-4 to control the polarization of macrophages. Modulation of the solubility of the silk films through regulation of β-sheet (crystalline) content enabled a short-term release (4–8 hours) of either cytokine, with smaller amounts released out to 24 hours. Altering the solubility of the films was accomplished by varying the time that the films were exposed to water vapor. The released IFN-γ or IL-4 induced polarization of THP-1 derived macrophages into the M1 or M2 phenotypes, respectively. The silk biomaterials were able to release enough IFN-γ or IL-4 to repolarize the macrophage from M1 to M2 and vice versa, demonstrating the well-established plasticity of macrophages. High β-sheet content films that are not soluble and do not release the trapped cytokines were also able to polarize macrophages that adhered to the surface through degradation of the silk protein. Chemically conjugating IFN-γ to silk films through disulfide bonds allowed for longer-term release to 10 days. The release of covalently attached IFN-γ from the films was also able to polarize M1 macrophages in vitro. Thus, the strategy described here offers new approaches to utilizing biomaterials for directing the polarization of macrophages.

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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

Cited by 66 publications

References 36 publications

CXC chemokine receptor 4 signaling upon co-activation with stromal cell-derived factor-1α and ubiquitin

CXC chemokine receptor 4 signaling upon co-activation with stromal cell-derived factor-1α and ubiquitin

Activation of CXCR7 Limits Atherosclerosis and Improves Hyperlipidemia by Increasing Cholesterol Uptake in Adipose Tissue

Controlled release of cytokines using silk-biomaterials for macrophage polarization

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