Neutrophil myeloperoxidase diminishes the toxic effects and mortality induced by lipopolysaccharide

Author:

Reber Laurent L.1234,Gillis Caitlin M.34ORCID,Starkl Philipp12,Jönsson Friederike34ORCID,Sibilano Riccardo12,Marichal Thomas12,Gaudenzio Nicolas12ORCID,Bérard Marion5ORCID,Rogalla Stephan67ORCID,Contag Christopher H.678910,Bruhns Pierre34ORCID,Galli Stephen J.128ORCID

Affiliation:

1. Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305

2. Sean N. Parker Center for Allergy and Asthma Research, Stanford University School of Medicine, Stanford, CA 94305

3. Department of Immunology, Unit of Antibodies in Therapy and Pathology, Institut Pasteur, 75015 Paris, France

4. Institut National de la Santé et de la Recherche Médicale, U1222, 75015 Paris, France

5. Animalerie Centrale, Institut Pasteur, 75015 Paris, France

6. Department of Pediatrics, Division of Neonatology, Stanford University School of Medicine, Stanford, CA 94305

7. Molecular Imaging Program at Stanford, Stanford University School of Medicine, Stanford, CA 94305

8. Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA 94305

9. Department of Radiology, Stanford University School of Medicine, Stanford, CA 94305

10. Department of Bioengineering, Stanford University School of Medicine, Stanford, CA 94305

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, PMNDTR mice, 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.

Funder

National Institutes of Health

European Commission

Institut National de la Santé et de la Recherche Médicale

Institut Carnot

European Research Council

Seventh Framework Programme

Austrian Academy of Sciences

Austrian Science Fund

Centre National de la Recherche Scientifique

Stanford University

National Center for Research Resources

Acteria Foundation

Fonds De La Recherche Scientifique-FNRS

Fondation pour la Recherche Médicale

Institut Pasteur

INSERM

Horizon 2020 Framework Programme

European Cooperation in Science and Technology

Tobacco-Related Disease Research Program

University of California

Stanford University School of Medicine

Publisher

Rockefeller University Press

Subject

Immunology,Immunology and Allergy

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