Wnt signaling: bone's defense against myeloma.

system has been provided. 6 Ligand internalization and degradation is part of the natural life cycle of signaling che-mokine receptors. 7 The new data from Car-dona 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 allo-steric inhibitors, which do not interfere with chemokine scavenging, desirable? Do waves of perturbations have a role in the activity of an-tagonists? Housekeeping by scavenging raises more issues than one would have expected. Conflict-of-interest disclosure: The authors declare no competing financial interests. ■mation and immunity by chemokine sequestration: decoys and more. control by the chemokine " interceptors " Duffy blood group antigen and D6. A silent chemokine receptor regulates steady-state leukocyte homing in vivo. Control of chemokine-guided cell migration by ligand se-questration. function for …