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 physiologic and pathologic 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 the organization and function of chemokine receptors and GPCRs in general include direct and indirect effects (Fig. 1). Here, we review how cholesterol and some key metabolites modulate functions of the chemokine system in multiple ways. We emphasize 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 modulating cell orchestration during inflammation, induction of an adaptive immune response, as well as to dampening an anti-tumor immune response.

Closely related, yet unique: Distinct homo- and heterodimerization patterns of G protein coupled chemokine receptors and their fine-tuning by cholesterol

“…POPC lipid bilayers serve as a robust membrane mimetic to study the interactions between membrane components in a controlled environment [ 20 ]. Based on the observation that cholesterol plays an important role in regulating chemokine receptor function and dimerization [ 53 , 55 – 63 ], the effect of cholesterol on the protein association was additionally studied.…”

“…from Förster or bioluminescence resonance energy transfer studies [ 54 ] (FRET or BRET, respectively)—could result from conformational changes in preexisting dimers upon ligand treatment instead of alterations of the binding affinity between receptors [ 14 , 21 , 35 ]. Furthermore, the modulation of chemokine receptor function by membrane cholesterol has been reported in several experimental studies [ 53 , 55 – 63 ].…”

The Activity of the Neutral Sphingomyelinase Is Important in T Cell Recruitment and Directional Migration

“…Cholesterol has recently been shown to directly modulate chemokine receptor function ( 35 ) and, therefore, organization of steady-state membrane domains enriched in ceramide might influence receptor organization. Association of CXCR4 with lipid rafts also was reported to be of functional importance ( 36 , 37 ), but did, however, not detectably differ between NSM KD and CTRL cells (not shown).…”

Remodeling our concept of chemokine receptor function: From monomers to oligomers

“…FRET analyses have determined that homo‐ and heterodimers are dynamic entities that depend on receptor expression, ligand binding, lipid composition of the cell membrane, coexpression of other proteins, and the environment that surrounds the cell. For example, PGE2‐mediated inflammatory signals induce CCR7 oligomerization on human MoDC, giving rise to efficient migration .…”