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Effects of sphingolipids overload on red blood cell properties in Gaucher disease.

ABSTRACT: Gaucher disease (GD) is a genetic disease with mutations in the GBA gene that encodes glucocerebrosidase causing complications such as anaemia and bone disease. GD is characterized by accumulation of the sphingolipids (SL) glucosylceramide (GL1), glucosylsphingosine (Lyso-GL1), sphingosine (Sph) and sphingosine-1-phosphate (S1P). These SL are increased in the plasma of GD patients and the associated complications have been attributed to the accumulation of lipids in macrophages. Our recent findings indicated that red blood cells (RBCs) and erythroid progenitors may play an important role in GD pathophysiology. RBCs abnormalities and dyserythropoiesis have been observed in GD patients. Moreover, we showed higher SL levels in the plasma and in RBCs from untreated GD patients compared with controls. In this study, we quantified SL in 16 untreated GD patients and 15 patients treated with enzyme replacement therapy. Our results showed that the treatment significantly decreases SL levels in the plasma and RBCs. The increased SL content in RBCs correlates with abnormal RBC properties and with markers of disease activity. Because RBCs lack glucocerebrosidase activity, we investigated how lipid overload could occur in these cells. Our results suggested that SL overload in RBCs occurs both during erythropoiesis and during its circulation in the plasma.

SUBMITTER: Dupuis L

PROVIDER: S-EPMC7520281 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

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Effects of sphingolipids overload on red blood cell properties in Gaucher disease.

Dupuis Lucie L Chipeaux Caroline C Bourdelier Emmanuelle E Martino Suella S Reihani Nelly N Belmatoug Nadia N Billette de Villemeur Thierry T Hivert Bénédicte B Moussa Fathi F Le Van Kim Caroline C de Person Marine M Franco Mélanie M

Journal of cellular and molecular medicine 20200807 17

Gaucher disease (GD) is a genetic disease with mutations in the GBA gene that encodes glucocerebrosidase causing complications such as anaemia and bone disease. GD is characterized by accumulation of the sphingolipids (SL) glucosylceramide (GL1), glucosylsphingosine (Lyso-GL1), sphingosine (Sph) and sphingosine-1-phosphate (S1P). These SL are increased in the plasma of GD patients and the associated complications have been attributed to the accumulation of lipids in macrophages. Our recent findi ...[more]

PMID: 32767726

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Project description:Sickle cell disease (SCD) is a genetic disease caused by a single mutation in the ?-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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Effects of sphingolipids overload on red blood cell properties in Gaucher disease.

Publications

Effects of sphingolipids overload on red blood cell properties in Gaucher disease.

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