Press releases

Endotoxic Shock: the Protective Role of Neutrophil Immune Cells

27 Apr 2017 | By Inserm (Newsroom) | Immunology, inflammation, infectiology and microbiology

In blue, the multilobed nuclei of neutrophils. In red, the myeloperoxidase (MPO) contained in cytoplasmic granules.

©Institut Pasteur

Researchers from Institut Pasteur and Inserm, in collaboration with Stanford University, have demonstrated the protective role of immune cells, called neutrophil granulocytes, in endotoxic shock – the component of septic shock related to the action of bacterial toxins. An effect thought to be based on the principal enzyme produced by these cells: myeloperoxidase. This discovery has been published in The Journal of Experimental Medicine.

Responsible for 50% of ICU deaths, septic shock is acute circulatory failure caused by an uncontrolled inflammatory response, which occurs in a context of serious infection. Septic shock involves, among other mechanisms, endotoxic shock: this is more particularly due to the action of the toxins produced by the bacteria responsible for the infection. Of these toxins, lipopolysaccharides (LPS) play a principal role in endotoxic shock by triggering the excessive, prolonged, and unbalanced immune cascade responsible for multiple organ failure.

Neutrophil granulocytes, which are white cells involved in the innate immune response and one of the body’s weapons in the fight against bacterial infection, have already been described as having antimicrobial activity. However, the scientific community thought that they could also have a harmful effect in the event of exposure to bacterial toxins such as LPS by exacerbating the associated inflammation and tissue damage.

Researchers from the “Antibodies in Therapy and Pathology” unit (Institut Pasteur/Inserm), in collaboration with Stanford University, have observed that, on the contrary, these neutrophils play a protective role against the inflammation triggered by LPS. As part of their work, they developed the first mouse model enabling a highly selective, inducible and reversible reduction in the neutrophil count.  With this they showed that neutrophil depletion made the mice more susceptible to the toxic effects of LPS, reducing their chances of survival and strongly activating their production of cytokines, the molecular messengers of inflammation.

More in detail, the researchers show that this protective capacity of the neutrophils is due to myeloperoxidase (MPO), the principal enzyme produced by these cells. “This protein, although routinely used as a marker of inflammation, does not increase it,” emphasizes Laurent Reber, one of the first authors of the paper. “On the contrary, it has a protective role.” “Patients with low MPO levels actually have a poorer prognosis in the event of septic shock,” adds Caitlin Gillis, the paper’s other first author.

“We have solved a paradox, in a way,” concludes Reber. “Neutrophils consistently combine antimicrobial activity and the ability to limit bacterial toxicity. The animal model that we have developed now means that we can continue to investigate the role of neutrophils in mechanisms of innate and adaptive immunity. We also want to try to understand how MPO acts in relation to LPS and why it has no effect on other bacterial toxins.”

This research was funded by Institut Pasteur, Inserm, Stanford University, ERC (MyeloSHOCK project) and NIH.

Neutrophil myeloperoxidase diminishes the toxic effects and mortality induced by lipopolysaccharide, The Journal of Experimental Medecine, 1er mai 2017. DOI : 10.1084/jem.20161238   Laurent L. Reber (1,2,8,10)*, Caitlin M. Gillis (8,10)*, Philipp Starkl (1,2), Friederike Jönsson (8,10), Riccardo Sibilano (1,2), Thomas Marichal (1,2), Nicolas Gaudenzio (1,2), Marion Bérard (9), Stephan Rogalla (3,4), Christopher H. Contag (3,4,5,6,7), Pierre Bruhns (8,10)** et Stephen J. Galli (1,2,5).**   (1) Department of Pathology, (2) Sean N. Parker Center for Allergy and Asthma Research, (3) Department of Pediatrics, Division of Neonatology, (4) Molecular Imaging Program at Stanford   (5) Department of Microbiology and Immunology, (6)Department of Radiology, and (7) Department of Bioengineering, Stanford University School  of Medicine, Stanford, CA 94305   (8) Department of Immunology, Unit of Antibodies in Therapy and Pathology and (9) Animalerie Centrale, Institut Pasteur, 75015 Paris, France   (10) Institut National de la Santé et de la Recherche Médicale, U1222, 75015 Paris, France * / ** : contribution égale de ces auteurs