Modulation of chemokine receptor function by cholesterol : new prospects for pharmacological intervention

Abstract

Chemokine receptors are seven transmembrane-domain receptors belonging to class A of G protein-coupled receptors (GPCRs). The receptors together with their chemokine ligands constitute the chemokine system, which is essential for directing cell migration and plays a crucial role in a variety of physiological and pathological processes. Given the importance of orchestrating cell migration, it is vital that chemokine receptor signaling is tightly regulated to ensure appropriate responses. Recent studies highlight a key role for cholesterol in modulating chemokine receptor activities. The steroid influences the spatial organization of GPCRs within the membrane bilayer, and consequently can tune chemokine receptor signaling. The effects of cholesterol on organization and function of chemokine receptors and GPCRs in general include direct and indirect effects. Here, we review how cholesterol and some key metabolites modulate the chemokine system functions by multiple ways. We emphasize on the role of cholesterol in chemokine receptor oligomerization, thereby promoting the formation of a signaling hub enabling integration of distinct signaling pathways at the receptor-membrane interface. Moreover, we discuss the role of cholesterol in stabilizing particular receptor conformations and its consequence for chemokine binding. Finally, we highlight how cholesterol accumulation, its deprivation or cholesterol metabolites contribute to modulate cell orchestration during inflammation, upon induction of an adaptive immune response, as well as in dampening the anti-tumor immune response.