title: Heme-induced neutrophil extracellular traps contribute to the pathogenesis of sickle cell disease.
abstract: Sickle cell disease (SCD) is characterized by recurring episodes of vascular occlusion in which neutrophil activation plays a major role. The disease is associated with chronic hemolysis with elevated cell-free hemoglobin and heme. The ensuing depletion of heme scavenger proteins leads to nonspecific heme uptake and heme-catalyzed generation of reactive oxygen species. Here, we have identified a novel role for heme in the induction of neutrophil extracellular trap (NET) formation in SCD. NETs are decondensed chromatin decorated by granular enzymes and are released by activated neutrophils. In humanized SCD mice, we have detected NETs in the lungs and soluble NET components in plasma. The presence of NETs was associated with hypothermia and death of these mice, which could be prevented and delayed, respectively, by dismantling NETs with DNase I treatment. We have identified heme as the plasma factor that stimulates neutrophils to release NETs in vitro and in vivo. Increasing or decreasing plasma heme concentrations can induce or prevent, respectively, in vivo NET formation, indicating that heme plays a crucial role in stimulating NET release in SCD. Our results thus suggest that NETs significantly contribute to SCD pathogenesis and can serve as a therapeutic target for treating SCD.
authors.affiliation: Ruth L. and David S. Gottesman Institute for Stem Cell and Regenerative Medicine Research, Albert Einstein College of Medicine, Bronx, NY;
authors.forename: Grace
authors.initials: G
authors.lastname: Chen
authors.affiliation: Ruth L. and David S. Gottesman Institute for Stem Cell and Regenerative Medicine Research, Albert Einstein College of Medicine, Bronx, NY;
authors.forename: Dachuan
authors.initials: D
authors.lastname: Zhang
authors.affiliation: Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA, and Department of Pediatrics, Harvard Medical School, Boston, MA;
authors.forename: Tobias A
authors.initials: TA
authors.lastname: Fuchs
authors.affiliation: Department of Pediatrics, Albert Einstein College of Medicine, Bronx, NY; and.
authors.forename: Deepa
authors.initials: D
authors.lastname: Manwani
authors.affiliation: Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA, and Department of Pediatrics, Harvard Medical School, Boston, MA; Division of Hematology/Oncology, Boston Children's Hospital, Boston, MA.
authors.forename: Denisa D
authors.initials: DD
authors.lastname: Wagner
authors.affiliation: Ruth L. and David S. Gottesman Institute for Stem Cell and Regenerative Medicine Research, Albert Einstein College of Medicine, Bronx, NY;
authors.forename: Paul S
authors.initials: PS
authors.lastname: Frenette
mesh_terms: D000328:Adult; D000755:Anemia, Sickle Cell / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D000818:Animals; D004195:Disease Models, Animal; D005110:Extracellular Space / Q000276:immunology / Q000378:metabolism; D006418:Heme / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D008168:Lung / Q000098:blood supply / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008833:Microcirculation; D018375:Neutrophil Activation / Q000502:physiology*; D009504:Neutrophils / Q000276:immunology* / Q000378:metabolism
chemical_list: D006418:Heme