Housekeeping by chemokine scavenging

A report in this issue of Blood reveals novel, unexpected regulatory mechanisms of the chemokine universe.

Chemokines are a complex superfamily of molecules that guide trafficking and positioning of hematopoietic and nonhematopoietic cells. In this issue of Blood, Cardona and colleagues show that mice genetically deficient in representative members of chemokine receptor classes have high levels of cognate ligands in blood and in inflamed tissues. Altered levels of promiscuous ligands perturb the system by affecting other receptors. This and previous scattered reports¹  suggest that signaling chemokine receptors internalize and scavenge cognate ligands, thus acting as rheostats and tuners of the system. These findings have broad implications for pathophysiology, interpretation of receptor-gene targeting experiments, and assessment of pharmacological inhibitors.

The chemokine system is a complex universe consisting of 42 genes encoding ligands and 20 signaling receptors, both having splice and processing variants; it also includes “silent” receptors that have alterations in sequence motifs essential for signaling (eg, the so-called DRY motif in the second intracellular loop), distinct spectra of ligands recognized, and peculiar tissue distribution, and can act as professional decoys and scavengers^2,3  (see figure). D6 binds most inflammatory CC chemokines, that is, those produced in response to inflammatory, immunological, or microbiological stimuli (eg, CCL2/MCP-1). CCX CKR binds homeostatic CC chemokines, which guide trafficking of lymphocytes to lymph nodes (eg, CCL19/ELC and CCL21/SLC). The Duffy Antigen Receptor for Chemokines (DARC; also known as Duffy antigen) binds inflammatory CC and CXC chemokines, and in addition to ligand degradation, it may also act as a facilitator of chemokine transfer across cellular barriers. Strong genetic data indicate that D6, CCX CKR, and to some extent, DARC are decoys and scavengers for chemokines that tune leukocyte trafficking under inflammatory (D6) and homeostatic (CCX CKR) conditions,^2-4  and recent evidence indicates that CXCR7, the second receptor for CXCL12/SDF1, also sharpens chemokine concentration and focuses the migration of zebrafish primordial germ cells by means of ligand scavenging.⁵  Thus, professional decoy receptors play an essential tuning role in the chemokine system; this paradigm could also extend beyond the chemokine system, as some evidence that the C5a receptor C5L2 plays a similar role in the complement system has been provided.⁶ 

Ligand internalization and degradation is part of the natural life cycle of signaling chemokine receptors.⁷  The new data from Cardona and colleagues clearly indicate that this pathway of disposal is physiologically relevant to the determination of chemokine levels in biological fluids and at least one inflamed tissue, the brain. The increased chemokine levels observed in mice deficient in a given receptor (CCR2) were shown to perturb the function of an unrelated receptor (CCR1). The explanation of this surprising result rests in the promiscuity and redundancy of the system. CCR2 ligands include CCL7/MCP-3, CCL8/MCP-2, and CCL13/MCP-4, which also bind CCR1; increased levels of these ligands are expected to down-regulate CCR1, as reported here. Thus, ligand internalization and degradation play key roles in tuning the system (see figure), and blocking some receptors may raise waves of perturbation in distant, unrelated receptors.

These and previous results have profound implications, ranging from pathophysiology to therapeutic intervention. This extensive set of data confirms and extends the concept that chemokine scavenging, be it performed by professionals or by conventional receptors^1,2,8  (see figure), is key to chemokine homeostasis in a complex system. The ligand scavenger function of chemokine decoy receptors is increased by exposure to increasing concentrations of the ligand,⁹  making them more efficient in this function when compared with signaling receptors, which are rapidly down-regulated by ligand engagement.⁷  The relative contribution of these 2 classes of receptors in keeping chemokine levels in check in vivo will have to be defined. The finding that blocking one receptor raises waves of perturbation of the system beyond the specific target, as shown here for CCR2 and CCR1, cautions against simplistic interpretations of data in gene-targeted mice. Moreover, it has implications for the pharmacology of chemokine receptors antagonists. With clinical approval of the CCR5 antagonist maraviroc, chemokine pharmacology has come of age.¹⁰  But are allosteric inhibitors, which do not interfere with chemokine scavenging, desirable? Do waves of perturbations have a role in the activity of antagonists? Housekeeping by scavenging raises more issues than one would have expected.