D6 as a Decoy and Scavenger Receptor for Inflammatory CC Chemokines in the Skin

Abstract

This chapter review recent studies, which have shed new light on the specificity, mode of action and actual function in the skin of one silent receptor, the D6 molecule, which behaves as a decoy and scavenger receptor for inflammatory CC chemokines. The chemokine system includes at least three seemingly silent receptors, Duffy antigen receptor for chemokines (DARC), D6, and CCX CKR. These molecules are structurally characterized by the lack of a canonical residue in the second transmembrane domain (TM) domain and of a canonical DRY motif in the second intracellular loop. There is strong evidence for DARC and D6 that these receptors do not activate conventional signaling responses. DARC has most likely a dual function, acting as a mechanism that facilitates transfer of chemokines across vascular endothelium and as a chemokine-buffering system under different circumstances. In vitro and in vivo evidence, including gene-targeted mice, is consistent with the view that D6 is a bona fide decoy receptor and scavenger for inflammatory CC chemokines. D6 is strategically located on lymphatic endothelial cells in the skin and other organs. Its ligand-independent shuttling from the plasma membrane to endocytic compartments where chemokines are targeted to degradation represents a unicum for 7 TM receptors. Thus, D6 is a genuine decoy and scavenger for inflammatory CC chemokines, uniquely adapted and located to tame inflammation in the skin and for draining lymph nodes.