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RED CELLS , IRON , AND ERYTHROPOIESIS Acid sphingomyelinase is activated in sickle cell erythrocytes and contributes to in fl ammatory microparticle generation in SCD

Sickle cell disease (SCD) is a hereditary blood disorder characterized by mutated hemoglobin molecules, which polymerize during deoxygenation to form fibers that deform the erythrocyte membrane. These red blood cells (RBCs) contribute to significant pathology including stroke, avascular necrosis, and vasculopathy. Because the sickling of the RBC membrane is pathognomonic in SCD, it is important to understand how modifications in membrane composition play a role in the disease. Sphingolipids are a class of lipids containing a backbone of sphingoid bases. They play diverse roles in cellular processes and are significant components of cell membranes. Sphingomyelin (SM), which comprises 10% of the mammalian plasma membrane, is degraded by the hydrolyzing enzyme sphingomyelinase (SMase). In recent studies, membrane curvature and associated increases in mechanical bending stresses in RBCs, activated SMase, thereby reducing SM and increasing ceramide. Production of ceramide has a direct effect on a wide range of cellular processes and alters production of other immediately descendent metabolites such as sphingosine and sphingosine 1-phosphate (S1P), which are key regulators of inflammation. Furthermore, SMase has been implicated in lipid microdomain formation, membrane fragility, vesiculation, and MP formation. Although the orientation of membrane lipids in SCD and other hemolytic anemias has been studied, the consequences of altered distribution and metabolism of sphingolipids have been largely unexplored. Sickle RBCs are a particularly interesting model system for the relationship between membrane stresses, inflammation, and sphingolipid metabolism. Acid SMase is secreted from endothelial and myeloid cells, and erythrocyte clearance and chronic inflammation, both of which occur in SCD and enhance the secretion of acid SMase. The role of acid SMase, and sphingolipid dysregulation more generally, has not been studied in the context of SCD. In this study, we hypothesized that dynamic shape distortion of RBCs and the accompanying increases in RBC membrane stresses enhance the activity of acid SMase in the blood, plasma, and RBCs of people living with SCD. This results in a significant increase in sphingosine and S1P in RBCs, as well as the generation of RBCderived MPs (Figure 1 and see supplemental Figure 1 on the Blood Web site). These factors enhance monocyte adhesion to endothelial cells and inflammatory cytokine production. Pharmacologic inhibition of acid SMase with a Food and Drug Administration-approved drug, amitriptyline, reducesMP generation and cytokine production. These results elucidate a novel mechanism for MP-mediated inflammatory cell activation in SCD. Additionally, these findings may be relevant to other hemolytic anemias and disorders rooted in aberrant RBC morphology.