The Outsiders: Emerging Roles of Ectonucleotidases in Inflammation

Research on the biological roles of ectonucleoidases has revealed that CD73, an ecto-5' nucleotidase, plays a special role in the extracellular conversion of adenosine monophosphate to adenosine-specifically, as a checkpoint that determines whether the extracellular environment is proinflammatory (characterized by adenosine 5'-triphosphate-mediated responses) or anti-inflammatory (adenosine-mediated responses). Inactivating or inhibiting CD73 attenuates the extracellular formation of adenosine, exacerbating the severity of various inflammatory diseases. In this issue of Science Translational Medicine, Flogel and colleagues showed that CD73 can be pharmacologically exploited to convert an inactive adenosine precursor to an active, anti-inflammatory adenosine analog. In addition to attenuating inflammation associated with collagen-induced arthritis in a mouse model, this prodrug approach was site-selective, because the metabolic conversion relies on CD73, which is up-regulated in the inflammatory locus (the joint).