title: Frontline Science: HMGB1 induces neutrophil dysfunction in experimental sepsis and in patients who survive septic shock.
abstract: Sepsis is accompanied by the initial activation of proinflammatory pathways and long-lasting immunosuppression that appears to contribute to late-occurring mortality. Although high-mobility group box 1 (HMGB1) is involved in many aspects of inflammation, its role in sepsis-induced immune suppression remains unclear. In this study, we examined HMGB1's contribution to neutrophil NADPH oxidase activity dysfunction and associated neutrophil-dependent bacterial clearance in mice subjected to sepsis and in patients who survive septic shock. Using a murine model of polymicrobial septic peritonitis, we demonstrated that treatment with anti-HMGB1 Ab significantly diminished sepsis-induced dysfunction of neutrophil NADPH oxidase activity. In a subsequent set of experiments, we found that blocking HMGB1 preserved the ability of neutrophils from patients recovering from septic shock to activate NADPH oxidase. Taken together, our data suggest that HMGB1 accumulation in the late phase of sepsis plays a specific role in the development of postsepsis immunosuppression and specifically affects neutrophil-dependent antibacterial defense mechanisms. Thus, blocking HMGB1 may be a promising therapeutic intervention to diminish the adverse effects of sepsis-induced immunosuppression.
authors.affiliation: Unité Mixte de Recherche (UMR) U917, INSERM, Rennes, France.|UMR U917, Université Rennes 1, Rennes, France.|Etablissement Français du sang, UMR U917, Rennes, France.|Suivi Immunologique des Thérapeutiques Innovantes, Pole de Biologie, Centre Hospitalier Universitaire (CHU) Rennes, Rennes, France.
authors.forename: Murielle
authors.initials: M
authors.lastname: Grégoire
authors.affiliation: Unité Mixte de Recherche (UMR) U917, INSERM, Rennes, France; jeanmarc.tadie@chu-rennes.fr.|UMR U917, Université Rennes 1, Rennes, France.|Etablissement Français du sang, UMR U917, Rennes, France.|Maladies Infectieuses et Réanimation Médicale, CHU Rennes, Rennes, France.|Centre d'Investigation Clinique (CIC) 1414, INSERM, Rennes, France.
authors.forename: Jean-Marc
authors.initials: JM
authors.lastname: Tadié
authors.affiliation: Unité Mixte de Recherche (UMR) U917, INSERM, Rennes, France.|UMR U917, Université Rennes 1, Rennes, France.|Etablissement Français du sang, UMR U917, Rennes, France.|Maladies Infectieuses et Réanimation Médicale, CHU Rennes, Rennes, France.|Centre d'Investigation Clinique (CIC) 1414, INSERM, Rennes, France.
authors.forename: Fabrice
authors.initials: F
authors.lastname: Uhel
authors.affiliation: Maladies Infectieuses et Réanimation Médicale, CHU Rennes, Rennes, France.|Centre d'Investigation Clinique (CIC) 1414, INSERM, Rennes, France.
authors.forename: Arnaud
authors.initials: A
authors.lastname: Gacouin
authors.affiliation: Service de Bactériologie, CHU Rennes, Rennes, France.
authors.forename: Caroline
authors.initials: C
authors.lastname: Piau
authors.affiliation: Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA; and.
authors.forename: Nathaniel
authors.initials: N
authors.lastname: Bone
authors.affiliation: Unité Mixte de Recherche (UMR) U917, INSERM, Rennes, France.|UMR U917, Université Rennes 1, Rennes, France.|Etablissement Français du sang, UMR U917, Rennes, France.|Maladies Infectieuses et Réanimation Médicale, CHU Rennes, Rennes, France.|Centre d'Investigation Clinique (CIC) 1414, INSERM, Rennes, France.
authors.forename: Yves
authors.initials: Y
authors.lastname: Le Tulzo
authors.affiliation: Office of the Dean, Wake Forest University School of Medicine, Winston-Salem, North Carolina, USA.
authors.forename: Edward
authors.initials: E
authors.lastname: Abraham
authors.affiliation: Unité Mixte de Recherche (UMR) U917, INSERM, Rennes, France.|UMR U917, Université Rennes 1, Rennes, France.|Etablissement Français du sang, UMR U917, Rennes, France.|Suivi Immunologique des Thérapeutiques Innovantes, Pole de Biologie, Centre Hospitalier Universitaire (CHU) Rennes, Rennes, France.
authors.forename: Karin
authors.initials: K
authors.lastname: Tarte
authors.affiliation: Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA; and.
authors.forename: Jaroslaw W
authors.initials: JW
authors.lastname: Zmijewski
mesh_terms: D000368:Aged; D000818:Animals; D016022:Case-Control Studies; D005260:Female; D024243:HMGB1 Protein / Q000378:metabolism*; D006801:Humans; D007960:Leukocyte Disorders / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D019255:NADPH Oxidases / Q000378:metabolism; D009504:Neutrophils / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D010538:Peritonitis / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D018805:Sepsis / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction
chemical_list: D024243:HMGB1 Protein; D008070:Lipopolysaccharides; D019255:NADPH Oxidases
keywords: HMGB1; NADPH oxidase; immunosuppression; neutrophils; sepsis