Detrimental effects of adenosine signaling in sickle cell disease

Yujin Zhang et al . discovered that the concentration of adenosine in the blood is increased both in a mouse model of sickle cell disease and in humans with this disease. Adenosine seems to have a pathological role in this disease, as it induced sickling of human erythrocytes through a mechanism involving activation of the A 2B adenosine receptor. Treatment of the mouse model of sickle cell disease with an agent to lower adenosine levels or with an A 2B adenosine receptor antagonist had beneficial effects, pointing to new therapeutic strategies for this disease. Hypoxia can act as an initial trigger to induce erythrocyte sickling and eventual end organ damage in sickle cell disease (SCD). Many factors and metabolites are altered in response to hypoxia and may contribute to the pathogenesis of the disease. Using metabolomic profiling, we found that the steady-state concentration of adenosine in the blood was elevated in a transgenic mouse model of SCD. Adenosine concentrations were similarly elevated in the blood of humans with SCD. Increased adenosine levels promoted sickling, hemolysis and damage to multiple tissues in SCD transgenic mice and promoted sickling of human erythrocytes. Using biochemical, genetic and pharmacological approaches, we showed that adenosine A 2B receptor (A 2B R)-mediated induction of 2,3-diphosphoglycerate, an erythrocyte-specific metabolite that decreases the oxygen binding affinity of hemoglobin, underlies the induction of erythrocyte sickling by excess adenosine both in cultured human red blood cells and in SCD transgenic mice. Thus, excessive adenosine signaling through the A 2B R has a pathological role in SCD. These findings may provide new therapeutic possibilities for this disease.