title: Kineret®/IL-1ra blocks the IL-1/IL-8 inflammatory cascade during recombinant Panton Valentine Leukocidin-triggered pneumonia but not during S. aureus infection.
abstract: OBJECTIVE
  Community-acquired Staphylococcus aureus necrotizing pneumonia is a life-threatening disease. Panton Valentine Leukocidin (PVL) has been associated with necrotizing pneumonia. PVL triggers inflammasome activation in human macrophages leading to IL-1β release. IL-1β activates lung epithelial cells to release IL-8. This study aimed to assess the relevance of this inflammatory cascade in vivo and to test the potential of an IL-1 receptor antagonist (IL-1Ra/Kineret) to decrease inflammation-mediated lung injury.
  
  
  METHODS
  We used the sequential instillation of Heat-killed S. aureus and PVL or S. aureus infection to trigger necrotizing pneumonia in rabbits. In these models, we investigated inflammation in the presence or absence of IL-1Ra/Kineret.
  
  
  RESULTS
  We demonstrated that the presence of PVL was associated with IL-1β and IL-8 release in the lung. During PVL-mediated sterile pneumonia, Kineret/IL-1Ra reduced IL-8 production indicating the relevance of the PVL/IL-1/IL-8 cascade in vivo and the potential of Kineret/IL-1Ra to reduce lung inflammation. However, Kineret/IL-1Ra was ineffective in blocking IL-8 production during infection with S. aureus. Furthermore, treatment with Kineret increased the bacterial burden in the lung.
  
  
  CONCLUSIONS
  Our data demonstrate PVL-dependent inflammasome activation during S.aureus pneumonia, indicate that IL-1 signaling controls bacterial burden in the lung and suggest that therapy aimed at targeting this pathway might be deleterious during pneumonia.
authors.affiliation: Vivexia, Dijon, France.
authors.forename: Delphine
authors.initials: D
authors.lastname: Labrousse
authors.affiliation: Université de Lyon, Lyon, France; INSERM U1111, Lyon, France; CNRS, UMR 5308, Lyon, France; Ecole Normale Supérieure, Lyon, France.
authors.forename: Magali
authors.initials: M
authors.lastname: Perret
authors.affiliation: Vivexia, Dijon, France.
authors.forename: Davy
authors.initials: D
authors.lastname: Hayez
authors.affiliation: Vivexia, Dijon, France.
authors.forename: Sonia
authors.initials: S
authors.lastname: Da Silva
authors.affiliation: Université de Lyon, Lyon, France; INSERM U1111, Lyon, France; CNRS, UMR 5308, Lyon, France; Ecole Normale Supérieure, Lyon, France.
authors.forename: Cédric
authors.initials: C
authors.lastname: Badiou
authors.affiliation: Université de Lyon, Lyon, France; INSERM U1111, Lyon, France; CNRS, UMR 5308, Lyon, France; Ecole Normale Supérieure, Lyon, France.
authors.forename: Florence
authors.initials: F
authors.lastname: Couzon
authors.affiliation: Université de Lyon, Lyon, France; INSERM U1111, Lyon, France; CNRS, UMR 5308, Lyon, France; Ecole Normale Supérieure, Lyon, France.
authors.forename: Michèle
authors.initials: M
authors.lastname: Bes
authors.affiliation: Infectious Diseases Department, University Hospital, Dijon, France.
authors.forename: Pascal
authors.initials: P
authors.lastname: Chavanet
authors.affiliation: Université de Lyon, Lyon, France; INSERM U1111, Lyon, France; CNRS, UMR 5308, Lyon, France; Ecole Normale Supérieure, Lyon, France.
authors.forename: Gérard
authors.initials: G
authors.lastname: Lina
authors.affiliation: Université de Lyon, Lyon, France; INSERM U1111, Lyon, France; CNRS, UMR 5308, Lyon, France; Ecole Normale Supérieure, Lyon, France.
authors.forename: François
authors.initials: F
authors.lastname: Vandenesch
authors.affiliation: Vivexia, Dijon, France; Infectious Diseases Department, University Hospital, Dijon, France.
authors.forename: Delphine
authors.initials: D
authors.lastname: Croisier-Bertin
authors.affiliation: Université de Lyon, Lyon, France; INSERM U1111, Lyon, France; CNRS, UMR 5308, Lyon, France; Ecole Normale Supérieure, Lyon, France.
authors.forename: Thomas
authors.initials: T
authors.lastname: Henry
mesh_terms: D000818:Animals; D001427:Bacterial Toxins / Q000633:toxicity*; D005098:Exotoxins / Q000633:toxicity*; D058847:Inflammasomes / Q000187:drug effects / Q000276:immunology; D053590:Interleukin 1 Receptor Antagonist Protein / Q000494:pharmacology* / Q000627:therapeutic use; D053583:Interleukin-1beta / Q000378:metabolism*; D016209:Interleukin-8 / Q000378:metabolism*; D007956:Leukocidins / Q000633:toxicity*; D008264:Macrophages / Q000187:drug effects / Q000276:immunology; D011023:Pneumonia, Staphylococcal / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism; D011817:Rabbits
chemical_list: D001427:Bacterial Toxins; D005098:Exotoxins; D058847:Inflammasomes; D053590:Interleukin 1 Receptor Antagonist Protein; D053583:Interleukin-1beta; D016209:Interleukin-8; D007956:Leukocidins; C078284:Panton-Valentine leukocidin