title: Role of IL-1β in experimental cystic fibrosis upon P. aeruginosa infection.
abstract: Cystic fibrosis is associated with increased inflammatory responses to pathogen challenge. Here we revisited the role of IL-1β in lung pathology using the experimental F508del-CFTR murine model on C57BL/6 genetic background (Cftr(tm1eur) or d/d), on double deficient for d/d and type 1 interleukin-1 receptor (d/d X IL-1R1-/-), and antibody neutralization. At steady state, young adult d/d mice did not show any signs of spontaneous lung inflammation. However, IL-1R1 deficiency conferred partial protection to repeated P. aeruginosa endotoxins/LPS lung instillation in d/d mice, as 50% of d/d mice succumbed to inflammation, whereas all d/d x IL-1R1-/- double mutants survived with lower initial weight loss and less pulmonary collagen and mucus production, suggesting that the absence of IL-1R1 signaling is protective in d/d mice in LPS-induced lung damage. Using P. aeruginosa acute lung infection we found heightened neutrophil recruitment in d/d mice with higher epithelial damage, increased bacterial load in BALF, and augmented IL-1β and TNF-α in parenchyma as compared to WT mice. Thus, F508del-CFTR mice show enhanced IL-1β signaling in response to P. aeruginosa. IL-1β antibody neutralization had no effect on lung homeostasis in either d/d or WT mice, however P. aeruginosa induced lung inflammation and bacterial load were diminished by IL-1β antibody neutralization. In conclusion, enhanced susceptibility to P. aeruginosa in d/d mice correlates with an excessive inflammation and with increased IL-1β production and reduced bacterial clearance. Further, we show that neutralization of IL-1β in d/d mice through the double mutation d/d x IL-1R1-/- and in WT via antibody neutralization attenuates inflammation. This supports the notion that intervention in the IL-1R1/IL-1β pathway may be detrimental in CF patients.
authors.affiliation: CNRS, UMR7355, Orleans, France; Experimental and Molecular Immunology and Neurogenetics, University of Orléans, Orléans, France.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Palomo
authors.affiliation: Artimmune, Orléans, France.
authors.forename: Tiffany
authors.initials: T
authors.lastname: Marchiol
authors.affiliation: CNRS, UMR7355, Orleans, France; Experimental and Molecular Immunology and Neurogenetics, University of Orléans, Orléans, France.
authors.forename: Julie
authors.initials: J
authors.lastname: Piotet
authors.affiliation: Artimmune, Orléans, France.
authors.forename: Louis
authors.initials: L
authors.lastname: Fauconnier
authors.affiliation: Artimmune, Orléans, France.
authors.forename: Marieke
authors.initials: M
authors.lastname: Robinet
authors.affiliation: CNRS, UMR7355, Orleans, France; Experimental and Molecular Immunology and Neurogenetics, University of Orléans, Orléans, France.
authors.forename: Flora
authors.initials: F
authors.lastname: Reverchon
authors.affiliation: CNRS, UMR7355, Orleans, France.
authors.forename: Marc
authors.initials: M
authors.lastname: Le Bert
authors.affiliation: Artimmune, Orléans, France.
authors.forename: Dieudonnée
authors.initials: D
authors.lastname: Togbe
authors.affiliation: Erasmus MC, Cell Biology department, Rotterdam, The Netherlands.
authors.forename: Ruvalic
authors.initials: R
authors.lastname: Buijs-Offerman
authors.affiliation: Erasmus MC, Cell Biology department, Rotterdam, The Netherlands.
authors.forename: Marta
authors.initials: M
authors.lastname: Stolarczyk
authors.affiliation: CNRS, UMR7355, Orleans, France; Experimental and Molecular Immunology and Neurogenetics, University of Orléans, Orléans, France.
authors.forename: Valérie F J
authors.initials: VF
authors.lastname: Quesniaux
authors.affiliation: Erasmus MC, Cell Biology department, Rotterdam, The Netherlands.
authors.forename: Bob J
authors.initials: BJ
authors.lastname: Scholte
authors.affiliation: CNRS, UMR7355, Orleans, France; Experimental and Molecular Immunology and Neurogenetics, University of Orléans, Orléans, France; Institute of Infectious Disease and Molecular Medicine, IDM, Cape Town, South Africa.
authors.forename: Bernhard
authors.initials: B
authors.lastname: Ryffel
mesh_terms: D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000382:microbiology; D003550:Cystic Fibrosis / Q000276:immunology* / Q000382:microbiology*; D016207:Cytokines / Q000378:metabolism; D006652:Histological Techniques; D053583:Interleukin-1beta / Q000378:metabolism*; D008168:Lung / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D018181:Mice, Inbred CFTR; D018345:Mice, Knockout; D009504:Neutrophils / Q000276:immunology; D011552:Pseudomonas Infections / Q000276:immunology* / Q000503:physiopathology; D011550:Pseudomonas aeruginosa; D053573:Receptors, Interleukin-1 Type I / Q000235:genetics; D015398:Signal Transduction / Q000276:immunology*; D018709:Statistics, Nonparametric; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D016207:Cytokines; C583355:IL1R1 protein, mouse; D053583:Interleukin-1beta; D053573:Receptors, Interleukin-1 Type I; D014409:Tumor Necrosis Factor-alpha