Atypical Roles of the Chemokine Receptor ACKR3/CXCR7 in Platelet Pathophysiology

Abstract

The manifold actions of the pro-inflammatory and regenerative chemokine CXCL12/SDF-1α are executed through the canonical GProteinCoupledReceptor CXCR4, and the non-canonical ACKR3/CXCR7. Platelets express CXCR4, ACKR3/CXCR7, and are a vital source of CXCL12/SDF-1α themselves. In recent years, a regulatory impact of the CXCL12-CXCR4-CXCR7 axis on platelet biogenesis, i.e., megakaryopoiesis, thrombotic and thrombo-inflammatory actions have been revealed through experimental and clinical studies. Platelet surface expression of ACKR3/CXCR7 is significantly enhanced following myocardial infarction (MI) in acute coronary syndrome (ACS) patients, and is also associated with improved functional recovery and prognosis. The therapeutic implications of ACKR3/CXCR7 in myocardial regeneration and improved recovery following an ischemic episode, are well documented. Cardiomyocytes, cardiac-fibroblasts, endothelial lining of the blood vessels perfusing the heart, besides infiltrating platelets and monocytes, all express ACKR3/CXCR7. This review recapitulates ligand induced differential trafficking of platelet CXCR4-ACKR3/CXCR7 affecting their surface availability, and in regulating thrombo-inflammatory platelet functions and survival through CXCR4 or ACKR3/CXCR7. It emphasizes the pro-thrombotic influence of CXCL12/SDF-1α exerted through CXCR4, as opposed to the anti-thrombotic impact of ACKR3/CXCR7. Offering an innovative translational perspective, this review also discusses the advantages and challenges of utilizing ACKR3/CXCR7 as a potential anti-thrombotic strategy in platelet-associated cardiovascular disorders, particularly in coronary artery disease (CAD) patients post-MI.

Emerging Roles of the Atypical Chemokine Receptor 3 (ACKR3) in Cardiovascular Diseases

“…Interestingly, treatment with ACKR3 agonist does not affect basal hemostatic or coagulation response. Thus, the anti-thrombotic actions of ACKR3 through the modulation of the platelet lipidome to limit metabolism and release of thrombotic and atherogenics mediators strengthened the therapeutic potential of ACKR3 in CVD ( 96 ). However, the mechanisms underlying this anti-thrombotic action of ACKR3 in platelets remain ascertained and further studies are needed.…”

Discovery and Development of First-in-Class ACKR3/CXCR7 Superagonists for Platelet Degranulation Modulation

“…Recently, the atypical chemokine receptor 3 (ACKR3), also known as CXC-chemokine receptor 7 (CXCR7), was shown to be expressed on platelets, modulating its function after binding of its endogenous ligand CXCL12 (also known as SDF-1; stromal cell-derived factor 1) and the subsequent recruitment of β-arrestin (Figure ). − Recent studies found that surface expression of ACKR3 is upregulated on platelets in patients with acute myocardial infarction and that increased ACKR3 expression improves the recovery in patients after myocardial infarction. , On the contrary, endothelial ACKR3 deletion hinders recovery of heart function after myocardial infarction, leading to increased mortality and infarct size rates, which is linked to the receptors’ role in proliferation and angiogenesis . These findings suggest ACKR3 as a promising therapeutic target for platelet-mediated thrombosis or other specific cardiovascular conditions.…”

“…Subsequently, β-arrestin recruitment leads to inhibition of platelet aggregation, suppression of pro-thrombotic response, and induction of the platelets’ lifespan. On the contrary, CXCR4 activation on platelets triggers platelet activation, aggregation, and thrombus formation. , …”

“…The activation of ACKR3 with its synthetic agonist, VUF11207 (Figure 2), has been shown to enhance platelet survival, decrease apoptosis, and inhibit platelet activation, degranulation, and aggregation, 18,23,24 thereby having an antithrombotic effect. 15,16 On the contrary, CXCR4, which is CXCR4 and ACKR3/CXCR7 signaling pathways in platelets and their functional activity.…”

“…On the contrary, CXCR4 activation on platelets triggers platelet activation, aggregation, and thrombus formation. 18,22 Figure 2. Examples of structures of reported ACKR3 agonists: AMD3100, 26 VUF11207, 27 compound III, 28 compound IV, 29,30 conolidine, 31 CCX777, 32 TC14012, 33,34 LIH383, 35 macrocyclic hexapeptide, 36 and amantamide.…”