Figure 1.

Figure 1 showing the possible role of CXCL12/CXCR4/ACKR3 axis in the pathogenesis of atherosclerosis. Black dots: oxLDL; EPCs: endothelial progenitor cells; VSMC: vascular smooth muscle cell. The black dot attached with box denotes lipid intake. Letters in italics are receptors; letters in bold are chemokines; arrows show proatherogenic role; dotted arrows show atheroprotective role. Large font CXCL12 denotes circulating CXCL12; small font CXCL12 denotes CXCL12 secreted from various cells. CXCR4/7 shows dimerization of two receptors or ambiguous role. Circulating CXCL12 is proatherogenic per se. But it also enhances the migration and proliferation of EPCs and EC repair through CXCR4, and adhesion through CXCR7. CXCL12/CXCR4 also increases the induction of eNOS phosphorylation leading to angiogenesis and plaque destabilization. CXCL12 also exerts a protective role by maintaining neutrophil homeostasis through CXCR4. Platelet-derived CXCL12 mediates platelet aggregation, increased foam cell formation, monocyte migration and adhesion through CXCR4/ACKR3 (depicted as CXCR4/7). But circulating CXCL12 enhances ACKR3 expression on platelets leading to increased survival of platelet and plaque stabilization and an atheroprotective action. ACKR3 and CXCR4 are also involved in plaque stabilization and fibrous cap formation through VSMC migration and proliferation. Both ACKR3 and CXCR4 are involved in uptake of ox-LDL and monocyte to macrophage induction and foam cell formation, which further attract inflammatory cells recruitment leading to atherogenic lipid core. Ox-LDL also aggravates CXCL12 release from macrophages. Detailed processes are not shown.