Purinergic signaling during sickle cell disease. In patients with sickle cell disease, extracellular adenosine levels are elevated. As an important antiinflammatory signal, Adora2a signaling on inflammatory cells (eg, on natural killer T cells [NKT-cells]) suppresses the innate immune response and limits inflammation and cellular injury. This endogenous antiinflammatory mechanism can be targeted for the treatment of ischemia and reperfusion injury such as occurs during vaso-occlusive syndrome in patients with sickle cell disease (eg, by using an Adora2a agonist therapeutically). However, noting a complication in the role of adenosine signaling during sickle cell disease, other studies that demonstrate that activation of the Adora2b by adenosine on erythrocytes increases their 2,3-DPG levels, thereby promoting red blood sickling.