Fig. 4.

Adenosine worsens sickle cell disease (SCD) by increasing 2,3-diphosphoglycerate (2,3-DPG) in red blood cells through the A_2B receptor. Increased amounts of ATP in circulation owing to chronic sickle red blood cell hemolysis and tissue damage from vasoocclusion are rapidly converted to adenosine. Activation of the A_2A receptor on natural killer T (NKT) cells suppresses the innate immune response and limits inflammation and cellular injury during ischemia and reperfusion injury. Top, in contrast, Zhang et al. [140] show that activation of the A_2B receptor by adenosine on erythrocytes increases 2,3-DPG levels through cAMP-dependent protein kinase A (PKA) activation, which reduces haemoglobin S (Hb S) oxygen affinity and promotes its polymerization and red blood cell sickling. Bottom, ‘crossroads’ of adenosine signaling determine positive or negative effects. The adenosine antagonist polyethylene glycol-modified adenosine deaminase (PEG-ADA) may be used to block adenosine signalling as a therapy for SCD; however, the development of specific agonists and inhibitors of these receptors may allow for selective inhibition of red blood cell A_2B-dependent 2,3-DPG production and activation of A_2A-dependent immune modulation to ease the disease more effectively. (Reproduced from [141] with permission from The Nature Publishing Group.)