title: Acid sphingomyelinase is activated in sickle cell erythrocytes and contributes to inflammatory microparticle generation in SCD.
abstract: Sphingolipids are a class of lipids containing a backbone of sphingoid bases that can be produced de novo through the reaction of palmitate and serine and further metabolized through the activity of various enzymes to produce intermediates with diverse roles in cellular processes and signal transduction. One of these intermediates, sphingosine 1-phosphate (S1P), is stored at high concentrations (1 μM) in red blood cells (RBCs) and directs a wide array of cellular processes mediated by 5 known G-protein coupled receptors (S1P1-S1P5). In this study, we show that RBC membrane alterations in sickle cell disease enhance the activation acid sphingomyelinase by 13%, resulting in increased production and storage of sphingosine (2.6-fold) and S1P (3.5-fold). We also show that acid sphingomyelinase enhances RBC-derived microparticle (MP) generation. These MPs are internalized by myeloid cells and promote proinflammatory cytokine secretion and endothelial cell adhesion, suggesting that potential crosstalk between circulating inflammatory cells and MPs may contribute to the inflammation-rooted pathogenesis of the disease. Treatment with amitriptyline reduces MP generation in vitro and in vivo and might be used to mitigate inflammatory processes in sickle cell disease.
authors: Department of Biomedical Engineering and.
authors: Anthony O
authors: AO
authors: Awojoodu
authors: Department of Biomedical Engineering and.
authors: Philip M
authors: PM
authors: Keegan
authors: Department of Biology, Georgia Institute of Technology, Atlanta, GA; and.
authors: Alicia R
authors: AR
authors: Lane
authors: Department of Biomedical Engineering and.
authors: Yuying
authors: Y
authors: Zhang
authors: Department of Pharmacology, The University of Virginia, Charlottesville, VA.
authors: Kevin R
authors: KR
authors: Lynch
authors: Department of Biomedical Engineering and.
authors: Manu O
authors: MO
authors: Platt
authors: Department of Biomedical Engineering and.
authors: Edward A
authors: EA
authors: Botchwey
mesh_terms: D000755:Anemia, Sickle Cell / Q000097:blood* / Q000201:enzymology* / Q000209:etiology; D000818:Animals; D002448:Cell Adhesion; D015815:Cell Adhesion Molecules / Q000097:blood; D055252:Cell-Derived Microparticles / Q000201:enzymology*; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000473:pathology; D004913:Erythrocytes, Abnormal / Q000201:enzymology*; D006451:Hemoglobin, Sickle / Q000235:genetics; D006801:Humans; D007249:Inflammation / Q000097:blood / Q000201:enzymology; D008246:Lysophospholipids / Q000097:blood; D020935:MAP Kinase Signaling System; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D008822:Mice, Transgenic; D013107:Sphingolipids / Q000097:blood; D013108:Sphingomyelin Phosphodiesterase / Q000097:blood*; D013110:Sphingosine / Q000031:analogs & derivatives / Q000097:blood
chemical_list: D015815:Cell Adhesion Molecules; D006451:Hemoglobin, Sickle; C095100:ICAM4 protein, human; D008246:Lysophospholipids; D013107:Sphingolipids; C060506:sphingosine 1-phosphate; D013108:Sphingomyelin Phosphodiesterase; D013110:Sphingosine