Regulation of the inflammatory chemochine decoy receptor-D6 ligand-stimulated Rab 11 dependent upregulation of surface express and scavenging

Regulation of the inflammatory chemokine decoy receptor D6: ligand-stimulated Rab11-dependent upregulation of surface expression and scavenging. D6 is a promiscuous chemokine scavenger receptor, expressed in lymphatic endothelium, that recognizes and targets to degradation most inflammatory CC chemokines. Fetal loss in animals and humans is frequently associated with inflammatory conditions. Here, I report that D6 plays a non-redundant role in the protection against fetal loss caused by systemic inflammation and antiphospholipid antibodies. D6 is expressed in placenta on invading extravillous trophoblasts and on the apical side of syncytiotrophoblast cells, at the very interface between maternal blood and fetus. Exposure of D6 / pregnant mice to LPS or antiphospholipid autoantibodies results in higher levels of inflammatory CC chemokines and increased leukocyte infiltrate in placenta, causing an increased rate of fetal loss, which is prevented by blocking inflammatory chemokines. I further demostrate that its scavenging activity relies on unique trafficking properties. Upon resting conditions, D6 constitutively cycles through both a rapid wortmannin-sensitive and a slower brefeldin A-sensitive pathway, and both Rab4 and Rab11 are required in order to maintain D6 surface expression. In contrast with conventional chemokine receptors that are downregulated by cognate ligands, chemokine engagement induces a dose-dependent brefeldin A-sensitive Rab11-dependent D6 redistribution to the cell membrane and a corresponding increase in chemokine degradation rate. Thus, the energy-expensive constitutive D6 cycling through Rab11 vesicles allows a rapid increase of chemokine scavenging activity by means of receptor redistribution to the plasma membrane upon ligand stimulation. In the absence of evidence of D6 regulation at the transcriptional level, this ligand-dependent optimization of D6 scavenger performance may represent an adaptive mechanism allowing D6 to control tissue inflammation.