title: HMGB1 promotes neutrophil extracellular trap formation through interactions with Toll-like receptor 4.
abstract: Although neutrophil extracellular traps (NETs) form to prevent dissemination of pathogenic microorganisms, excessive release of DNA and DNA-associated proteins can also perpetuate sterile inflammation. In this study, we found that the danger-associated molecular pattern protein high-mobility group box 1 (HMGB1) can induce NET formation. NET formation was found after exposure of wild-type and receptor for advanced glycation end products-deficient neutrophil to HMGB1, whereas deficiency of Toll-like receptor (TLR)4 diminished the ability of neutrophils to produce NETs. Incubation of neutrophils with HMGB1 significantly increased the amount of DNA and histone 3 released as well as intracellular histone 3 citrullination, a signaling event that precedes chromatin decondensation. In vivo, neutrophils isolated from bronchoalveolar lavages of mice exposed to LPS and HMGB1 showed consistently greater ability to produce NETs compared with pulmonary neutrophils from mice that received LPS alone. In contrast, mice treated with LPS and neutralizing antibody to HMGB1 had decreased amounts of the inflammatory cytokines TNF-α and macrophage inflammatory protein 2, as well as of free DNA and histone 3 in bronchoalveolar lavage fluids. Airway neutrophils from LPS-exposed mice that had been treated with anti-HMGB1 antibodies showed decreased citrullination of histone 3. These results demonstrate that interactions between HMGB1 and TLR4 enhance the formation of NETs and provide a novel mechanism through which HMGB1 may contribute to the severity of neutrophil-associated inflammatory conditions.
authors: Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
authors: Jean-Marc
authors: JM
authors: Tadie
authors: Hong-Beom
authors: HB
authors: Bae
authors: Shaoning
authors: S
authors: Jiang
authors: Dae Won
authors: DW
authors: Park
authors: Celeste P
authors: CP
authors: Bell
authors: Huan
authors: H
authors: Yang
authors: Jean-Francois
authors: JF
authors: Pittet
authors: Kevin
authors: K
authors: Tracey
authors: Victor J
authors: VJ
authors: Thannickal
authors: Edward
authors: E
authors: Abraham
authors: Jaroslaw W
authors: JW
authors: Zmijewski
mesh_terms: D055371:Acute Lung Injury / Q000276:immunology* / Q000378:metabolism; D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D004247:DNA / Q000378:metabolism; D004195:Disease Models, Animal; D024243:HMGB1 Protein / Q000378:metabolism*; D006657:Histones / Q000378:metabolism; D007249:Inflammation; D008070:Lipopolysaccharides / Q000276:immunology; D008168:Lung / Q000276:immunology / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018375:Neutrophil Activation; D009504:Neutrophils / Q000276:immunology*; D051197:Toll-Like Receptor 4 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
chemical_list: D024243:HMGB1 Protein; D006657:Histones; D008070:Lipopolysaccharides; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D004247:DNA