DARC and D6: silent partners in chemokine regulation?

Chemokine receptors adorn the surface of leukocytes and other cell types ready to translate the extracellular chemokine environment into functional cellular outcomes. However, there are several molecules that, in many respects, look like chemokine receptors, but which do not have the ability to confer chemotactic potential to cell lines. This apparent silence spurred the search for signalling-independent functions and led to the development of new paradigms of chemokine regulation. In this review, we summarise the experimental basis for these ideas focussing on DARC and D6, the most studied members of this group of molecules. We discuss data generated using in vitro systems and genetically deficient mice, include results from observational human studies, and summarise the key findings of recent research. We take a critical look at current models of in vivo function highlighting important gaps in our knowledge and demonstrating that there is still much to find out about these enigmatic molecules.