Role and implications of the CXCL12/CXCR4/CXCR7 axis in atherosclerosis: still a debate

Atherosclerosis is one of the leading causes of mortality and morbidity worldwide. Chemokines and their receptors are implicated in the pathogenesis of atherosclerosis. CXCL12 is a member of the chemokine family exerting a myriad role in atherosclerosis through its classical CXCR4 and atypical ACKR3 (CXCR7) receptors. The modulatory and regulatory functional spectrum of CXCL12/CXCR4/ACKR3 axis in atherosclerosis spans from proatherogenic, prothrombotic and proinflammatory to atheroprotective, plaque stabilizer and dyslipidemia rectifier. This diverse continuum is executed in a wide range of biological units including endothelial cells (ECs), progenitor cells, macrophages, monocytes, platelets, lymphocytes, neutrophils and vascular smooth muscle cells (VSMCs) through complex heterogeneous and homogenous coupling of CXCR4 and ACKR3 receptors, employing different downstream signalling pathways, which often cross-talk among themselves and with other signalling interactomes. Hence, a better understanding of this structural and functional heterogeneity and complex phenomenon involving CXCL12/CXCR4/ACKR3 axis in atherosclerosis would not only help in formulation of novel therapeutics, but also in elucidation of the CXCL12 ligand and its receptors, as possible diagnostic and prognostic biomarkers. Key messages The role of CXCL12 per se is proatherogenic in atherosclerosis development and progression. The CXCL12 receptors, CXCR4 and ACKR3 perform both proatherogenic and athero-protective functions in various cell types Due to functional heterogeneity and cross talk of CXCR4 and ACKR3 at receptor level and downstream pathways, regional boosting with specific temporal and spatial modulators of CXCL12, CXCR4 and ACKR3 need to be explored.

Automated summary

Atherosclerosis, a leading cause of mortality and morbidity globally, involves the complex interplay of chemokines and their receptors, particularly CXCL12 and its receptors CXCR4 and ACKR3. The CXCL12/CXCR4/ACKR3 axis in atherosclerosis has a dual role in promoting and protecting against atherosclerosis in various cell types. Due to the functional heterogeneity and cross talk of CXCR4 and ACKR3 at receptor level and downstream pathways, targeted modulation of CXCL12, CXCR4, and ACKR3 with specific spatial and temporal factors is a potential area for further exploration in atherosclerosis research.