Dual CCR5/CCR2 targeting: opportunities for the cure of complex disorders

Abstract

The chemokine system mediates acute inflammation by driving leukocyte migration to damaged or infected tissues. However, elevated expression of chemokines and their receptors can contribute to chronic inflammation and malignancy. Thus, great effort has been taken to target these molecules. The first hint of the druggability of the chemokine system was derived from the role of chemokine receptors in HIV infection. CCR5 and CXCR4 function as essential co-receptors for HIV entry, with the former accounting for most new HIV infections worldwide. Not by chance, an anti-CCR5 compound, maraviroc, was the first FDA-approved chemokine receptor-targeting drug. CCR5, by directing leukocytes to sites of inflammation and regulating their activation, also represents an important player in the inflammatory response. This function is shared with CCR2 and its selective ligand CCL2, which constitute the primary chemokine axis driving the recruitment of monocytes/macrophages to inflammatory sites. Both receptors are indeed involved in the pathogenesis of several immune-mediated diseases, and dual CCR5/CCR2 targeting is emerging as a more efficacious strategy than targeting either receptor alone in the treatment of complex human disorders. In this review, we focus on the distinctive and complementary contributions of CCR5 and CCR2/CCL2 in HIV infection, multiple sclerosis, liver fibrosis and associated hepatocellular carcinoma. The emerging therapeutic approaches based on the inhibition of these chemokine axes are highlighted.

Keywords: AIDS; Autoimmunity; Chemokine receptor antagonist; Liver disease; Neuroinflammation; Therapeutic antibody.

Fig. 1

Schematic view of the role of CCR5 and CCR2/CCL2 in the pathogenesis of HIV infection. a Infection by HIV occurs when the virus attaches to a susceptible cell and fuses with the cell membrane. The players in this process are the CD4 receptor and a co-receptor, mainly CCR5. The level of viral infection correlates with the number of CCR5 molecules expressed on cell surface, independently from their conformation. HIV-infected cells then release CCL2, which enhances HIV replication with cell type-dependent mechanisms, recruits new HIV target cells and mediates the transmigration of HIV-infected monocytes into the central nervous system (CNS) across the blood–brain barrier (BBB), thus contributing to neuroinflammation, neuronal damage and HIV-associated neurocognitive disorders (HAND). b Individuals homozygous for the CCR5Δ32 allele are protected against HIV infection, whereas those heterozygous for CCR5Δ32 progress slowly toward the disease. Natural Abs to CCR5 also  confer protection against HIV infection, as they have been found in HIV-exposed seronegative (HESN) subjects and long-term non-progressors (LTNP). Pharmacological blockade of CCR5 through chemical antagonists, chemokine ligands, mAbs, and gene editing may as well protect from HIV infection

Fig. 2

Schematic representation of the multiple roles of CCR5 and CCR2/CCL2 in inflammation, axonal damage and repair in MS. a In the lymph node, CCR5 ligands secreted by activated antigen-presenting cell (APCs) and CD4⁺ T helper cells mediate CD8⁺ T cells recruitment and T cell activation. CCR5 ligands also promote trans-endothelial migration and crossing of the blood–brain barrier (BBB) by circulating CCR5⁺ effector T cells and phagocytes. CNS invading Th1 cells and monocytes, as well as CNS resident innate immune cells such as microglia and astrocytes, co-express CCR2 and CCR5. Their ligands CCL2, CCL3, CCL4 and CCL5 are also up-regulated in MS lesions where they can be produced by activated microglia, astrocytes and neurons. CCL2 and CCR5 ligands secreted in situ amplify local autoimmune/inflammatory responses ultimately leading to demyelination and axonal damage. b Besides mediating demyelination and neuronal damage (left), CCL2 and CCR5 ligands contribute to remyelination and damage repair (right). CCR5⁺CCR2⁺ macrophages are essential for the clearance of myelin debris. CCL2 also enhances oligodendrocyte precursor (OPC) mobility, enabling them to populate demyelinated lesions, where they differentiate into myelin sheath-forming oligodendrocytes (ODC)

Fig. 3

Schematic model of the role of CCR5 and CCR2/CCL2 in liver fibrosis and tumor development. a Hepatocyte histological changes during the progression from a healthy liver to non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), cirrhosis and hepatocellular carcinoma (HCC). b Contribution of CCR5 and CCR2/CCL2 to the major pathogenic events leading to liver inflammation and fibrosis. Activated Kupffer cells (KCs) and damaged hepatocytes secrete CCR2 and CCR5 ligands, which mediate monocyte recruitment, their differentiation into macrophages, and activation of hepatic stellate cells (HSCs), thus contributing to inflammation and extracellular matrix (ECM) deposition. c Contribution of CCR5 and CCR2/CCL2 to HCC progression. In the tumor microenvironment, CCR2 and CCR5 ligands secreted by KCs, damaged hepatocytes and tumor cells promote tumor growth and mediates monocyte recruitment and their maturation into tumor-associated macrophages (TAMs) with pro-angiogenic and pro-fibrotic features; the infiltration of myeloid-derived suppressor cells (MDSCs), thus contributing to immunosuppression; the progression of primary tumors towards metastases by promoting the migration, invasion and epithelial–mesenchymal transition of HCC cells. On the other hand, these chemokine axes also promote the infiltration of effectors cells, which contributes to tumor eradication