Dual CCR5/CCR2 targeting: opportunities for the cure of complex disorders.
Laura FantuzziMaria TagliamonteMaria Cristina GauzziLopalco LuciaPublished in: Cellular and molecular life sciences : CMLS (2019)
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.
Keyphrases
- dendritic cells
- regulatory t cells
- liver fibrosis
- antiretroviral therapy
- oxidative stress
- multiple sclerosis
- inflammatory response
- hiv infected
- human immunodeficiency virus
- endothelial cells
- cancer therapy
- emergency department
- hiv positive
- gene expression
- drug induced
- immune response
- hiv aids
- liver failure
- peripheral blood
- lipopolysaccharide induced
- liver injury
- extracorporeal membrane oxygenation
- acute respiratory distress syndrome
- respiratory failure
- mechanical ventilation