title: Sickle cell disease increases high mobility group box 1: a novel mechanism of inflammation.
abstract: High mobility group box 1 (HMGB1) is a chromatin-binding protein that maintains DNA structure. On cellular activation or injury, HMGB1 is released from activated immune cells or necrotic tissues and acts as a damage-associated molecular pattern to activate Toll-like receptor 4 (TLR4). Little is known concerning HMGB1 release and TLR4 activity and their role in the pathology of inflammation of sickle cell disease (SCD). Circulating HMGB1 levels were increased in both humans and mice with SCD compared with controls. Furthermore, sickle plasma increased HMGB1-dependent TLR4 activity compared with control plasma. HMGB1 levels were further increased during acute sickling events (vasoocclusive crises in humans or hypoxia/reoxygenation injury in mice). Anti-HMGB1 neutralizing antibodies reduced the majority of sickle plasma-induced TLR4 activity both in vitro and in vivo. These findings show that HMGB1 is the major TLR4 ligand in SCD and likely plays a critical role in SCD-mediated inflammation.
authors.affiliation: Division of Pediatric Surgery, Department of Surgery, Children's Research Institute, and.
authors.forename: Hao
authors.initials: H
authors.lastname: Xu
authors.affiliation: Children's Research Institute, and Divisions of Hematology, Pulmonary and Emergency Medicine, Department of Pediatrics, Clinical and Translational Science Institute of Southeastern Wisconsin, Medical College of Wisconsin, Milwaukee, WI; Blood Research Institute, Blood Center of Wisconsin, Milwaukee, WI; and.
authors.forename: Nancy J
authors.initials: NJ
authors.lastname: Wandersee
authors.affiliation: Children's Research Institute, and Divisions of Hematology, Pulmonary and Emergency Medicine, Department of Pediatrics, Blood Research Institute, Blood Center of Wisconsin, Milwaukee, WI; and.
authors.forename: YiHe
authors.initials: Y
authors.lastname: Guo
authors.affiliation: Division of Pediatric Surgery, Department of Surgery.
authors.forename: Deron W
authors.initials: DW
authors.lastname: Jones
authors.affiliation: Blood Research Institute, Blood Center of Wisconsin, Milwaukee, WI; and.
authors.forename: Sandra L
authors.initials: SL
authors.lastname: Holzhauer
authors.affiliation: Divisions of Hematology, Pulmonary and Emergency Medicine, Department of Pediatrics, Clinical and Translational Science Institute of Southeastern Wisconsin, Medical College of Wisconsin, Milwaukee, WI; Blood Research Institute, Blood Center of Wisconsin, Milwaukee, WI; and.
authors.forename: Madelyn S
authors.initials: MS
authors.lastname: Hanson
authors.affiliation: Children's Research Institute, and Divisions of Hematology, Pulmonary and Emergency Medicine, Department of Pediatrics.
authors.forename: Evans
authors.initials: E
authors.lastname: Machogu
authors.affiliation: Children's Research Institute, and Divisions of Hematology, Pulmonary and Emergency Medicine, Department of Pediatrics, Clinical and Translational Science Institute of Southeastern Wisconsin, Medical College of Wisconsin, Milwaukee, WI;
authors.forename: David C
authors.initials: DC
authors.lastname: Brousseau
authors.affiliation: Clinical and Translational Science Institute of Southeastern Wisconsin, Medical College of Wisconsin, Milwaukee, WI; Department of Biophysics, Medical College of Wisconsin, Milwaukee, WI.
authors.forename: Neil
authors.initials: N
authors.lastname: Hogg
authors.affiliation: Division of Pediatric Surgery, Department of Surgery, Children's Research Institute, and.
authors.forename: John C
authors.initials: JC
authors.lastname: Densmore
authors.affiliation: Division of Pediatric Surgery, Department of Surgery.
authors.forename: Sushma
authors.initials: S
authors.lastname: Kaul
authors.affiliation: Children's Research Institute, and Divisions of Hematology, Pulmonary and Emergency Medicine, Department of Pediatrics, Clinical and Translational Science Institute of Southeastern Wisconsin, Medical College of Wisconsin, Milwaukee, WI; Blood Research Institute, Blood Center of Wisconsin, Milwaukee, WI; and.
authors.forename: Cheryl A
authors.initials: CA
authors.lastname: Hillery
authors.affiliation: Division of Pediatric Surgery, Department of Surgery, Children's Research Institute, and Clinical and Translational Science Institute of Southeastern Wisconsin, Medical College of Wisconsin, Milwaukee, WI;
authors.forename: Kirkwood A
authors.identifier: http://orcid.org/0000-0001-9706-5297
authors.initials: KA
authors.lastname: Pritchard
mesh_terms: D000755:Anemia, Sickle Cell / Q000276:immunology / Q000378:metabolism*; D000818:Animals; D005786:Gene Expression Regulation; D024243:HMGB1 Protein / Q000378:metabolism*; D006801:Humans; D000860:Hypoxia / Q000473:pathology; D007249:Inflammation / Q000378:metabolism*; D008024:Ligands; D051379:Mice; D008810:Mice, Inbred C57BL; D010100:Oxygen / Q000378:metabolism; D015398:Signal Transduction; D051197:Toll-Like Receptor 4 / Q000378:metabolism*
chemical_list: D024243:HMGB1 Protein; C585491:HMGB1 protein, human; C582808:HMGB1 protein, mouse; D008024:Ligands; C495345:TLR4 protein, human; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D010100:Oxygen