Myeloperoxidase in the pathogenesis of sickle cell disease

Sickle cell disease (SCD) is an inherited disorder characterized by abnormal hemoglobin molecules that cause the sickling of red blood cells (RBCs) which occlude blood vessels, increase hemolysis, and leads to chronic inflammation. Accumulating evidence has strongly linked SCD and other inflammatory conditions to the persistent activation of neutrophils which generate the antimicrobial enzyme myeloperoxidase (MPO) that produces hypohalous acids such as hypochlorous acid (HOCl) and hypothiocyanous acid. The MPO-HOCl system can induce oxidative damage of erythrocytes and vasculature through the accumulation of toxic free iron and the deficiency of nitric oxide (NO) and zinc (Zn), which are common features observed in SCD. MPO is also a crucial regulator in neutrophil extracellular trap (NET) formation that significantly contributes to SCD pathogenesis and vaso-occlusive crises. The objective of this review is to discuss the potential role of MPO-HOCl in SCD pathophysiology and summarize the current state of knowledge regarding the role of NETs, oxidative stress, and NO in SCD. Here, we highlight the novel pathway of MPO-HOCl in SCD pathology that drives NET formation, alters hemoglobin oxidation states, accelerates hemolysis, generates free iron and protein aggregation through hemoglobin heme destruction, and increases vascular constriction through endothelin-1 upregulation and nitric oxide depletion.