Oxidative stress in sickle cell disease; more than a DAMP squib

Sickle cell disease (SCD) is a monogenetic disorder marked by hemolytic anemia and vaso-occlusive complications. The hallmark of SCD is the intracellular polymerization of sickle hemoglobin (HbS) after deoxygenation, and the subsequent characteristic shape change (sickling) of red cells. Vaso-occlusion occurs after endothelial activation, expression of adhesion molecules and subsequent adhesion of leucocytes and sickle erythrocytes to the vascular wall. Here we review how oxidative stress from various sources influences this process. Emerging evidence points towards a dominant mechanism in which innate immune receptors, such as Toll like receptor 4, activate nicotinamide adenine dinucleotide phosphate (NADPH) oxidases to produce reactive oxygen species (ROS) which in turn enables downstream pro-inflammatory signaling and subsequent endothelial activation. By serving as an iron donor for the Fenton reaction, heme radically increases the amount of ROS further, thereby increasing the signal originating from the innate immune receptor and downstream effects of innate immune receptor activation. In SCD this results in the production of pro-inflammatory cytokines, endothelial activation and leucocyte adhesion, and eventually vaso-occlusion. Any intervention to stop this cascade, including Toll like receptor blockade, NADPH oxidase inhibition, ROS reduction, heme scavenging, iron chelation, or anti-adhesion molecule antibodies has been successfully used in pre-clinical studies and holds promise for patients with SCD.