G-Protein Coupled Receptor Targeting on Myeloid Cells in Atherosclerosis

Abstract

Atherosclerosis, the underlying cause of the majority of cardiovascular diseases (CVDs), is a lipid-driven, inflammatory disease of the large arteries. Gold standard therapy with statins and the more recently developed proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors have improved health conditions among CVD patients by lowering low density lipoprotein (LDL) cholesterol. Nevertheless, a substantial part of these patients is still suffering and it seems that 'just' lipid lowering is insufficient. The results of the Canakinumab Anti-inflammatory Thrombosis Outcome Study (CANTOS) have now proven that inflammation is a key driver of atherosclerosis and that targeting inflammation improves CVD outcomes. Therefore, the identification of novel drug targets and development of novel therapeutics that block atherosclerosis-specific inflammatory pathways have to be promoted. The inflammatory processes in atherosclerosis are facilitated by a network of immune cells and their subsequent responses. Cell networking is orchestrated by various (inflammatory) mediators which interact, bind and induce signaling. Over the last years, G-protein coupled receptors (GPCRs) emerged as important players in recognizing these mediators, because of their diverse functions in steady state but also and specifically during chronic inflammatory processes - such as atherosclerosis. In this review, we will therefore highlight a selection of these receptors or receptor sub-families mainly expressed on myeloid cells and their role in atherosclerosis. More specifically, we will focus on chemokine receptors, both classical and atypical, formyl-peptide receptors, the chemerin receptor 23 and the calcium-sensing receptor. When information is available, we will also describe the consequences of their targeting which may hold promising options for future treatment of CVD.

Keywords: G-protein coupled receptors; atherosclerosis; cardiovascular disease; myeloid cells; therapy.

FIGURE 1

Schematic overview of the involvement of the various GPCRs in atherosclerosis development. For each receptor the key processes, as well as agonists/antagonists are summarized and depicted over three main phases of atherosclerosis development; mobilization, leukocyte recruitment and plaque progression. Receptors of the same GPCR-subfamily are clustered together and categorized from I till V. (I) Chemokine receptor CXCR4 causes migration of leukocytes toward its ligand CXCL12. Additionally, upon LDL stimulation CXCL1 is released by endothelial cells causing myeloid cells, which carry CXCR2 on their surface to migrate toward the endothelium. CCL2 and CX3CL1 mediate the recruitment of monocytes expressing CCR2 and CX3CR1, respectively. In line with this, monocytes expressing CCR5 are recruited to the lesion by CCL5. (II) Monocytes show a CaSR-dependent increase of chemotaxis toward CCL2 upon stimulation with calcium. (III) FPR2 is mostly expressed on myeloid cells and has several contradictory effects, please see Table 1. FPR2-agonists like Ac2-26, an Annexin A1 peptide, and Annexin A1 reduce monocyte/neutrophil recruitment. (IV) ChemR23 maintains a M1 macrophage phenotype and stimulates pDC migration and infiltration into atherosclerotic plaques. (V) ACKR3 expression is upregulated in lesional macrophages which engulf modified lipids resulting in foam cell formation. ACKR3, atypical chemokine receptor 3; CAD, coronary artery disease; CaSR, calcium-sensing receptor; CCR, C-C chemokine receptor; CCL, C-C chemokine ligand; ChemR23, chemerin receptor 23; CRP, C-reactive protein; CXCR, C-X-C chemokine receptor; CX3CR1, CX3C chemokine receptor 1; CXCL, C-X-C chemokine ligand; CX3CL1, CX3C chemokine ligand 1; FPR2, formyl-peptide receptor 2; HIV, human immunodeficiency virus; LDL, low-density lipoprotein; oxLDL, oxidized LDL; pDC, plasmacytoid dendritic cell.