Mitochondrial retention in mature red blood cells from patients with sickle cell disease is associated with stress erythropoiesis but not with proinflammatory state

Sickle cell disease (SCD) is a hemoglobinopathy characterized by the occurrence of vaso‐occlusive events, severe chronic hemolytic anemia, and ultimately chronic complications and end‐organ damages. 1 , 2 , 3 SCD pathophysiology has been shown to be extremely complex, resulting from microcirculatory dysfunctions associated with altered vaso‐regulation and activation of inflammation cascades responsible of sterile inflammatory state, endothelial and neutrophil activation, and release of neutrophil extracellular trap (NET). 1 , 4 , 5 , 6 More recently, a dysfunctional erythropoiesis has been described in SS patients characterized by high level of reticulocytes, increased apoptosis at the later stage of erythropoiesis, and abnormal retention of mitochondria in red blood cells (RBCs). 7 , 8 , 9 , 10 , 11 , 12 , 13 It is noteworthy that the functionality of these mitochondria in mature sickle RBCs remains controversial 11 , 12 and mechanisms responsible for the mitochondrial retention during erythropoiesis have not been identified. Besides these unanswered points, several groups reported in vitro evidence that plasma mitochondrial DNA released by hemolysis of these abnormal RBCs could trigger type I interferon production 12 and NET release in SCD patients. 13 Altogether, these studies suggested that mitochondrial DNA from sickle mature RBCs could play a key role in the proinflammatory state associated with the disease.