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

Abstract

Chemokines, and their receptors play a crucial role in the pathophysiology of cardiovascular diseases (CVD). Chemokines classically mediate their effects by binding to G-protein-coupled receptors. The discovery that chemokines can also bind to atypical chemokine receptors (ACKRs) and initiate alternative signaling pathways has changed the paradigm regarding chemokine-related functions. Among these ACKRs, several studies have highlighted the exclusive role of ACKR3, previously known as C-X-C chemokine receptor type 7 (CXCR7), in CVD. Indeed, ACKR3 exert atheroprotective, cardioprotective and anti-thrombotic effects through a wide range of cells including endothelial cells, platelets, inflammatory cells, fibroblasts, vascular smooth muscle cells and cardiomyocytes. ACKR3 functions as a scavenger receptor notably for the pleiotropic chemokine CXCL12, but also as a activator of different pathways such as β-arrestin-mediated signaling or modulator of CXCR4 signaling through the formation of ACKR3-CXCR4 heterodimers. Hence, a better understanding of the precise roles of ACKR3 may pave the way towards the development of novel and improved therapeutic strategies for CVD. Here, we summarize the structural determinant characteristic of ACKR3, the molecules targeting this receptor and signaling pathways modulated by ACKR3. Finally, we present and discuss recent findings regarding the role of ACKR3 in CVD.

Keywords: ACKR3; atypical chemokine receptors; cardiovascular diseases; chemokine; signalling.

Figure 1

Schematic representation of signaling pathways for ACKR3. Chemokines ligands CXCL12 and CXCL11 can induce phosphorylation of ACKR3 by GRK or others kinases, the recruitment of β-arrestins and trigger intracellular G-protein independent signaling. ACKR3 is also able to scavenge various ligands (CXCL12, CXCL11, ADM, PAMP, PAMP12, opioїd peptides) at the cell surface, internalized these ligands which subsequently result in degradation in lysosome while the receptor recycles to the cell membrame. ACKR3 is also able to interact with G-proteins without to lead to their activation. However, in two specific cellular types, primary rodent astrocytes and human glioma cells, ACKR3 can be coupled to Gα-protein and triggers PLC and MAPK activation. GRK, G-protein receptor kinase; ADM, adrenomedullin; PAMP, proadrenomedullinN-terminal 20 peptide; PLC, phospholipase C; MAPK, mitogen-activated protein kinase. (Figure created with BioRender.com).

Figure 2

Role of ACKR3 in the infarcted heart. ACKR3 expression is increased in several cells of the heart following myocardial infarction, and can play multiple roles after activation by endogenous and exogenous ligands. ACKR3 exerts cardioprotective effects by acting either as a rheostat for certain ligands through scavenging activity or as a co-partner through dimerization with other receptors. In addition, ACKR3 may trigger activation of β-arrestin-dependent pathways. (Figure created with BioRender.com).