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J Exp Med. 2017 May 1;214(5):1249-1258. doi: 10.1084/jem.20161238. Epub 2017 Apr 6.

Neutrophil myeloperoxidase diminishes the toxic effects and mortality induced by lipopolysaccharide.

Author information

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.
11
Department of Immunology, Unit of Antibodies in Therapy and Pathology, Institut Pasteur, 75015 Paris, France sgalli@stanford.edu bruhns@pasteur.fr.
12
Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305 sgalli@stanford.edu bruhns@pasteur.fr.

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.

PMID:
28385925
PMCID:
PMC5413333
DOI:
10.1084/jem.20161238
[Indexed for MEDLINE]
Free PMC Article

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