Studies on Airway Inflammation and Remodeling in Chronic Lung Disease The EGFR-ADAM17 axis controls inflammatory responses in Cystic Fibrosis and Chronic Obstructive Pulmonary Disease

Cystic fibrosis is associated with increased inflammatory responses to pathogen challenge. Here we revisited the role of IL-1b in lung pathology using the experimental F508del-CFTR murine model on C57BL/6 genetic background(Cftr or d/d), on double deficient for d/d and type 1 interleukin-1 receptor (d/d XIL-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 alld/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-1b and TNF-a in parenchyma as compared to WT mice. Thus, F508del-CFTR mice show enhanced IL-1b signaling in response to P. aeruginosa. IL-1b 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-1b antibody neutralization. In conclusion, enhanced susceptibility to P. aeruginosa in d/d mice correlates with an excessive inflammation and with increased IL-1b production and reduced bacterial clearance. Further, we show thatneutralization of IL-1b 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-1b pathway may be detrimental in CF patients.OPEN ACCESS Citation: Palomo J, Marchiol T, Piotet J,Fauconnier L, Robinet M, et al. (2014) Role of IL-1b in Experimental Cystic Fibrosis upon P.aeruginosa Infection. PLoS ONE 9(12): e114884.doi:10.1371/journal.pone.0114884 Editor: Min Wu, University of North Dakota, UnitedStates of America Received: October 3, 2014 Accepted: November 14, 2014 Published: December 12, 2014 Copyright: ! 2014 Palomo et al. This is an open-access article distributed under the terms of theCreative Commons Attribution License, whichpermits unrestricted use, distribution, and repro-duction in any medium, provided the original authorand source are credited. Data Availability: The authors confirm that all dataunderlying the findings are fully available withoutrestriction. All relevant data are within the paper. Funding: This study was part of the Europeanproject n 1̊0IM1016 financed by the Frenchassociation ‘‘Vaincre La Mucoviscidose’’, supportedby the ERASMUS Medical Center of Rotterdam(The Netherlands), and by Région Centre (Respigproject) and CNRS of Orléans (France). RBO wassupported by the Dutch CF foundation NCFS; MSwas supported by the Dutch Lung foundation(Longfonds 3.3.10.027). The funders had no role instudy design, data collection and analysis, decisionto publish, or preparation of the manuscript. Competing Interests: The authors confirm thatco-author Bernhard Ryffel is a PLOS ONE EditorialBoard member. And the authors confirm that theyhave declared that no competing interests exist. T.Marchiol, L. Fauconnier, M. Robinet and D. Togbeare employed by the commercial company‘‘Artimmune’’, but this does not alter the authors’adherence to PLOS ONE policies on sharing dataand materials. PLOS ONE | DOI:10.1371/journal.pone.0114884 December 12, 20141 / 17