The CXCL12/CXCR4 chemokine ligand/receptor axis in cardiovascular disease

Abstract

The chemokine receptor CXCR4 and its ligand CXCL12 play an important homeostatic function by mediating the homing of progenitor cells in the bone marrow and regulating their mobilization into peripheral tissues upon injury or stress. Although the CXCL12/CXCR4 interaction has long been regarded as a monogamous relation, the identification of the pro-inflammatory chemokine macrophage migration inhibitory factor (MIF) as an important second ligand for CXCR4, and of CXCR7 as an alternative receptor for CXCL12, has undermined this interpretation and has considerably complicated the understanding of CXCL12/CXCR4 signaling and associated biological functions. This review aims to provide insight into the current concept of the CXCL12/CXCR4 axis in myocardial infarction (MI) and its underlying pathologies such as atherosclerosis and injury-induced vascular restenosis. It will discuss main findings from in vitro studies, animal experiments and large-scale genome-wide association studies. The importance of the CXCL12/CXCR4 axis in progenitor cell homing and mobilization will be addressed, as will be the function of CXCR4 in different cell types involved in atherosclerosis. Finally, a potential translation of current knowledge on CXCR4 into future therapeutical application will be discussed.

Keywords: CXCL12; CXCR4; CXCR7; MIF; atherosclerosis; cardiovascular disease; myocardial infarction; restenosis.

Figure 1

Sequence similarities of different CXCL12/SDF-1 isoforms. Six isoforms of CXCL12/SDF-1 have been described to date, which share a common N-terminal amino acid sequence, but a distinct C-terminus. Shown is the single letter amino acid code for all CXCL12 isoforms, with the shared N-terminal sequence highlighted in green. Indications of specific amino acid positions inform on the length of the different CXCL12 isoforms: α (89 aa), β (93 aa), γ (119 aa), δ (140 aa), ε (90 aa), and ϕ (100 aa). aa, amino acid; SDF, stromal cell-derived factor.

Figure 2

The CXCL12 signaling network. CXCL12 employs two distinct receptors, CXCR4 and CXCR7. CXCR4 additionally acts a receptor for MIF, whereas CXCR7 can also bind CXCL11. Generally, stimulation of CXCR4 triggers preferentially G-protein-coupled signaling, whereas activation of CXCR7 or the CXCR4/CXCR7 complex induces β-arrestin-mediated signaling. Internalization of the receptors CXCR4 and CXCR7, and subsequent recycling to the cell membrane, is also mediated through β-arrestin. Upon binding to CXCR7, CXCL12 is internalized and subjected to lysosomal degradation. AKT, PKB, Protein kinase B; MAPK, mitogen-activated protein kinase; MIF, macrophage migration inhibitory factor; PI3K, phosphatidylinositide 3-kinase; G_αβγ, heterotrimeric G-protein consisting of the subunits α, β, and γ.

Figure 3

Involvement of CXCR4 in CAD. The chemokine receptor CXCR4 plays a role in angiogenesis. Furthermore, it is an important regulator of homing, mobilization and survival of progenitor cells. This has linked CXCR4 with a role in myocardial ischemia and injury-induced restenosis, but its significance in the context of native atherosclerosis remains unclear. CXCR4 has also been reported to mediate leukocyte chemotaxis in specific inflammatory diseases. A similar role in inflammatory cell recruitment has been suggested in the context of myocardial ischemia, but the importance of CXCR4-induced leukocyte recruitment to atherosclerotic lesions in vivo remains to be further addressed. The current view mainly emphasizes the involvement of inflammatory chemokines instead of the homeostatic chemokine CXCL12 in mediating atherogenic leukocyte recruitment. However, CXCR4 can mediate both CXCL12- and MIF-induced chemotaxis of B- and T-cells in vitro, and is also expressed on a subset of monocytes, requiring further research of its function in atherogenic leukocyte recruitment in vivo. Also, it remains unclear which cell type-specific functions of CXCR4 may be important in context of atherosclerosis, with currently only scarce information on potential cellular functions in most cell types present in atherosclerotic lesions. For more details, we refer to the text. Green arrows indicate beneficial effects, red arrows indicate detrimental effects. The interrelation between different pathologies belonging to CAD is visualized. The lower panels indicate relevance of CXCR4-involving cell type-specific functions to atherosclerotic plaque formation. bFGF, basic fibroblast growth factor; CAD, coronary artery disease; H2S, hydrogen sulfide; M-CSF, macrophage colony stimulating factor; MMP, matrix metallopeptidase; oxLDL, oxidized low-density lipoprotein; VEGF, vascular endothelial growth factor.