Neutrophil myeloperoxidase diminishes the toxic effects and mortality induced by lipopolysaccharide

Laurent L Reber (1, 2, 3) , Caitlin Gillis (1) , Philipp Starkl (2, 3) , Friederike Jönsson (1) , Riccardo Sibilano (2, 3) , Thomas Marichal (2, 3) , Nicolas Gaudenzio (2, 3) , Marion Bérard (4) , Stephan Rogalla (5, 6) , Christopher H Contag (5, 6, 7, 8, 9) , Pierre Bruhns (1) , Stephen J Galli (2, 7, 3)

1 Anticorps en thérapie et pathologie - Antibodies in Therapy and Pathology
2 Department of Pathology [Stanford]
3 Sean N. Parker Center for Allergy and Asthma Research [Stanford]
4 Animalerie centrale (Plate-forme)
5 Department of Pediatrics [Stanford]
6 MIPS - Molecular Imaging Program at Stanford
7 Department of Microbiology and Immunology [Stanford]
8 Department of Radiology [Stanford]
9 Department of Bioengineering [Stanford]

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.

Domains: Life Sciences [q-bio]; Immunology; Innate immunity

Laurent L Reber, Caitlin Gillis, Philipp Starkl, Friederike Jönsson, Riccardo Sibilano, et al.. Neutrophil myeloperoxidase diminishes the toxic effects and mortality induced by lipopolysaccharide. Journal of Experimental Medicine, 2017, 214 (5), pp.1249 - 1258. ⟨10.1084/jem.20161238⟩. ⟨pasteur-01928589⟩