title: Neutrophil myeloperoxidase diminishes the toxic effects and mortality induced by lipopolysaccharide.
abstract: Neutrophils have crucial antimicrobial functions but are also thought to contribute to tissue injury upon exposure to bacterial products, such as lipopolysaccharide (LPS). To study the role of neutrophils in LPS-induced endotoxemia, we developed a new mouse model,PMNDTRmice, in which injection of diphtheria toxin induces selective neutrophil ablation. Using this model, we found, surprisingly, that neutrophils serve to protect the host from LPS-induced lethal inflammation. This protective role was observed in conventional and germ-free animal facilities, indicating that it does not depend on a particular microbiological environment. Blockade or genetic deletion of myeloperoxidase (MPO), a key neutrophil enzyme, significantly increased mortality after LPS challenge, and adoptive transfer experiments confirmed that neutrophil-derived MPO contributes importantly to protection from endotoxemia. Our findings imply that, in addition to their well-established antimicrobial properties, neutrophils can contribute to optimal host protection by limiting the extent of endotoxin-induced inflammation in an MPO-dependent manner.
authors.affiliation: Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305.|Sean N. Parker Center for Allergy and Asthma Research, Stanford University School of Medicine, Stanford, CA 94305.|Department of Immunology, Unit of Antibodies in Therapy and Pathology, Institut Pasteur, 75015 Paris, France.|Institut National de la Santé et de la Recherche Médicale, U1222, 75015 Paris, France.
authors.forename: Laurent L
authors.initials: LL
authors.lastname: Reber
authors.affiliation: Department of Immunology, Unit of Antibodies in Therapy and Pathology, Institut Pasteur, 75015 Paris, France.|Institut National de la Santé et de la Recherche Médicale, U1222, 75015 Paris, France.
authors.forename: Caitlin M
authors.identifier: 0000-0001-9892-206X
authors.initials: CM
authors.lastname: Gillis
authors.affiliation: Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305.|Sean N. Parker Center for Allergy and Asthma Research, Stanford University School of Medicine, Stanford, CA 94305.
authors.forename: Philipp
authors.initials: P
authors.lastname: Starkl
authors.affiliation: Department of Immunology, Unit of Antibodies in Therapy and Pathology, Institut Pasteur, 75015 Paris, France.|Institut National de la Santé et de la Recherche Médicale, U1222, 75015 Paris, France.
authors.forename: Friederike
authors.identifier: 0000-0002-1667-8065
authors.initials: F
authors.lastname: Jönsson
authors.affiliation: Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305.|Sean N. Parker Center for Allergy and Asthma Research, Stanford University School of Medicine, Stanford, CA 94305.
authors.forename: Riccardo
authors.initials: R
authors.lastname: Sibilano
authors.affiliation: Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305.|Sean N. Parker Center for Allergy and Asthma Research, Stanford University School of Medicine, Stanford, CA 94305.
authors.forename: Thomas
authors.initials: T
authors.lastname: Marichal
authors.affiliation: Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305.|Sean N. Parker Center for Allergy and Asthma Research, Stanford University School of Medicine, Stanford, CA 94305.
authors.forename: Nicolas
authors.identifier: 0000-0002-5648-509X
authors.initials: N
authors.lastname: Gaudenzio
authors.affiliation: Animalerie Centrale, Institut Pasteur, 75015 Paris, France.
authors.forename: Marion
authors.identifier: 0000-0001-8709-7762
authors.initials: M
authors.lastname: Bérard
authors.affiliation: Department of Pediatrics, Division of Neonatology, Stanford University School of Medicine, Stanford, CA 94305.|Molecular Imaging Program at Stanford, Stanford University School of Medicine, Stanford, CA 94305.
authors.forename: Stephan
authors.identifier: 0000-0002-1311-2672
authors.initials: S
authors.lastname: Rogalla
authors.affiliation: Department of Pediatrics, Division of Neonatology, Stanford University School of Medicine, Stanford, CA 94305.|Molecular Imaging Program at Stanford, Stanford University School of Medicine, Stanford, CA 94305.|Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA 94305.|Department of Radiology, Stanford University School of Medicine, Stanford, CA 94305.|Department of Bioengineering, Stanford University School of Medicine, Stanford, CA 94305.
authors.forename: Christopher H
authors.initials: CH
authors.lastname: Contag
authors.affiliation: Department of Immunology, Unit of Antibodies in Therapy and Pathology, Institut Pasteur, 75015 Paris, France sgalli@stanford.edu bruhns@pasteur.fr.|Institut National de la Santé et de la Recherche Médicale, U1222, 75015 Paris, France.
authors.forename: Pierre
authors.identifier: 0000-0002-4709-8936
authors.initials: P
authors.lastname: Bruhns
authors.affiliation: Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305 sgalli@stanford.edu bruhns@pasteur.fr.|Sean N. Parker Center for Allergy and Asthma Research, Stanford University School of Medicine, Stanford, CA 94305.|Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA 94305.
authors.forename: Stephen J
authors.identifier: 0000-0001-5736-5340
authors.initials: SJ
authors.lastname: Galli
mesh_terms: D000818:Animals; D000906:Antibodies / Q000276:immunology; D004195:Disease Models, Animal; D019446:Endotoxemia / Q000276:immunology* / Q000401:mortality; D008070:Lipopolysaccharides / Q000633:toxicity*; D051379:Mice; D009504:Neutrophils / Q000201:enzymology / Q000502:physiology*; D009195:Peroxidase / Q000502:physiology*; D018805:Sepsis / Q000276:immunology
chemical_list: D000906:Antibodies; D008070:Lipopolysaccharides; D009195:Peroxidase