• Katrin Anne Becker, Xiang Li, Aaron Seitz, Joerg Steinmann, Anne Koch, Edward Schuchman, Markus Kamler, Michael J Edwards, Charles C Caldwell, and Erich Gulbins.
• Department of Molecular Biology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.
• Cell. Physiol. Biochem. 2017 Jan 1; 43 (4): 1603-1616.

Background/AimsCystic fibrosis (CF) is dominated by chronic inflammation and infection of the lung resulting in lung destruction and early death of patients. The lungs of CF patients are characterized by a massive accumulation of neutrophils. It requires definition why these massive numbers of neutrophils fail to eliminate typical CF pathogens like Staphylococcus aureus and Pseudomonas aeruginosa (P. aeruginosa) in CF lungs.MethodsWe determined ceramide, sphingosine and reactive oxygen species (ROS) in neutrophils from wildtype and CF mice and determined the effect of sphingosine and ROS alone or in combination on killing of different P. aeruginosa strains.ResultsWe demonstrate that wildtype neutrophils are able to kill non-mucoid and mucoid clinical P. aeruginosa strains, while neutrophils from CF mice are insufficient to kill these P. aeruginosa strains, although both types of neutrophils infected with P. aeruginosa produce comparable levels of superoxide. All three analyzed P. aeruginosa strains are resistant to reactive oxygen species. The inability of CF neutrophils to kill P. aeruginosa is caused by a marked decrease of surface sphingosine levels in CF neutrophils. Wildtype neutrophils contain much higher concentrations of surface sphingosine than CF neutrophils. Further, wildtype neutrophils, but not CF neutrophils, release sphingosine, most likely as microparticles, upon infection. Sphingosine kills P. aeruginosa in vitro at low micromolar concentrations. Reconstitution of sphingosine in CF neutrophils restores their ability to kill these pathogens, demonstrating the significance of sphingosine for bacterial killing.ConclusionThe data provide evidence for a new paradigm explaining how neutrophils kill ROS-resistant P. aeruginosa, i.e. by sphingosine that kills P. aeruginosa at low concentrations. This mechanism is defective in CF neutrophils.© 2017 The Author(s). Published by S. Karger AG, Basel.

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