CHEMOKINES, CYTOKINES, AND INTERLEUKINS Regulation of D6 chemokine scavenging activity by ligand- and Rab11-dependent surface up-regulation

The decoy receptor D6 plays a nonredundant role in the control of inflammatory processes through scavenging of inflammatory chemokines. However it remains unclear how it is regulated. Here we show that D6 scavenging activity relies on unique trafficking properties. Under resting conditions, D6 constitutively recycled through both a rapid wortmannin (WM)–sensitive and a slower brefeldin A (BFA)–sensitive pathway, maintaining low levels of surface expression that required both Rab4 and Rab11 activities. In contrast to “conventional” chemokine receptors that are downregulated by cognate ligands, chemokine engagement induced a dose-dependent BFA-sensitive Rab11-dependent D6 redistribution to the cell membrane and a corresponding increase in chemokine degradation rate. Thus, the energyexpensive constitutive D6 cycling through Rab11 vesicles allows a rapid, ligand concentration–dependent increase of chemokine scavenging activity by receptor redistribution to the plasma membrane. D6 is not regulated at a transcriptional level in a variety of cellular contexts, thus liganddependent optimization of its scavenger performance represents a rapid and unique mechanism allowing D6 to control inflammation. (Blood. 2008;112:493-503)