The Red Blood Cell—Inflammation Vicious Circle in Sickle Cell Disease
Résumé
Sickle cell disease (SCD) is a genetic disease caused by a single mutation in the
β-globin gene, leading to the production of an abnormal hemoglobin called hemoglobin
S (HbS), which polymerizes under deoxygenation, and induces the sickling of red
blood cells (RBCs). Sickled RBCs are very fragile and rigid, and patients consequently
become anemic and develop frequent and recurrent vaso-occlusive crises. However, it
is now evident that SCD is not only a RBC rheological disease. Accumulating evidence
shows that SCD is also characterized by the presence of chronic inflammation and
oxidative stress, participating in the development of chronic vasculopathy and several
chronic complications. The accumulation of hemoglobin and heme in the plasma, as a
consequence of enhanced intravascular hemolysis, decreases nitric oxide bioavailability
and enhances the production of reactive oxygen species (ROS). Heme and hemoglobin
also represent erythrocytic danger-associated molecular pattern molecules (eDAMPs),
which may activate endothelial inflammation through TLR-4 signaling and promote the
development of complications, such as acute chest syndrome. It is also suspected that
heme may activate the innate immune complement system and stimulate neutrophils to
release neutrophil extracellular traps. A large amount of microparticles (MPs) from various
cellular origins (platelets, RBCs, white blood cells, endothelial cells) is also released into
the plasma of SCD patients and participate in the inflammation and oxidative stress
in SCD. In turn, this pro-inflammatory and oxidative stress environment further alters
the RBC properties. Increased pro-inflammatory cytokine concentrations promote the
activation of RBC NADPH oxidase and, thus, raise the production of intra-erythrocyte
ROS. Such enhanced oxidative stress causes deleterious damage to the RBC membrane
and further alters the deformability of the cells, modifying their aggregation properties.
These RBC rheological alterations have been shown to be associated to specific
SCD complications, such as leg ulcers, priapism, and glomerulopathy. Moreover,
RBCs positive for the Duffy antigen receptor for chemokines may be very sensitive
to various inflammatory molecules that promote RBC dehydration and increase RBC
adhesiveness to the vascular wall. In summary, SCD is characterized by a vicious circle
between abnormal RBC rheology and inflammation, which modulates the clinical severity
of patients
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