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12 May 2017

Immunology: the protective role of neutrophil immune cells in endotoxic shock

A collaborative work led by the Institut Pasteur and Stanford University demonstrates the surprising protective role of neutrophil immune cells in endotoxic shock, the septic shock caused by bacterial toxins. This protective role appears to rely on myeloperoxidase, the main enzyme synthesised by neutrophil immune cells. Researchers have published their findings in The Journal of Experimental Medicine, May 2017.

Septic shock is a serious issue in medicine: it is responsible for half of all death in intensive care services. Characterized by an excessive and uncontrolled inflammatory response to infectious pathogens, septic shock induces a critical reduction in tissue perfusion and abnormal cellular metabolism, leading to acute failure of multiple organs. One of the underlying mechanisms is the endotoxic shock caused by the bacterial toxins during infection: bacterial lipopolysaccharides (LPS) trigger the excessive, prolonged and unbalanced immune response.
In order to fight against bacterial infections, the organism possesses specialised blood cells involved in innate immune response. Among them, the polynuclear neutrophils. Despite their well-established antimicrobial properties, one however thought that neutrophils had a harmful action during exposition to bacterial LPS. Literature describes neutrophils as worsening inflammation and tissue damages associated to LPS.
The results obtained by Pierre Bruhns’ team at the Institut Pasteur (Antibodies in Therapy and Pathology - Inserm U1222, Department of Immunology) and their co-workers at Stanford (Stephen J. Galli, Stanford University School of Medicine, Department of Pathology) show quite the reverse: neutrophils can contribute to optimal host protection after LPS-induced inflammation.
They have developed a new mouse model allowing the induction of neutrophils selective ablation, in a reversible and transient manner. Using this model, they experimentally provoked LPS-induced lethal inflammation and demonstrated a protective role of neutrophils. Reducing their number in mice makes the animals more likely to be subject to the toxic effects of LPS, with acute activation of cytokines production, the molecular messenger of inflammation, and reduction in survival in germ-free animal facilities. More specifically, they showed that the protective capacity of neutrophils relies on a key neutrophil enzyme: myeloperoxidase (MPO). « This protein, which is yet commonly used as an inflammation biomarker, does not reinforce inflammation. On the contrary, it has a protective role » Laurent Reber, co-first author, says. « Patients with low level of MPO actually have a worse prognosis in case of a septic shock » Caitlin Gillis adds, the other co-first author.
« In a way, we have solved a paradox » Reber sums up. « Neutrophils consistently associate antimicrobial activity and capacity to limit the toxicity of bacteria. Our animal model can now allow us to investigate further the function of neutrophils regarding innate and adaptive immunity. We also want to know how MPO acts with the bacterial lipopolysaccharides and why it has no effect on other bacterial toxins. »


Polynuclear neutrophils in blue. Myeloperoxidase (MPO), located inside cytoplasmic granules, in red ©Institut Pasteur

Neutrophil myeloperoxidase diminishes the toxic effects and mortality induced by lipopolysaccharide
Laurent L. Reber, Caitlin M. Gillis, Philipp Starkl, Friederike Jönsson, Riccardo Sibilano, Thomas Marichal, Nicolas Gaudenzio, Marion Bérard, Stephan Rogalla, Christopher H. Contag, Pierre Bruhns, Stephen J. Galli
J Exp Med. 2017 May 1; 214(5): 1249–1258. doi: 10.1084/jem.20161238
PMCID: PMC5413333 (delayed release - embargo - will be available in PMC on November 1, 2017)

From Institut Pasteur press release (27 April 2017) - in French