title: Neutrophil proteases alter the interleukin-22-receptor-dependent lung antimicrobial defence.
abstract: Chronic obstructive pulmonary disease (COPD) is punctuated by episodes of infection-driven acute exacerbations. Despite the life-threatening nature of these exacerbations, the underlying mechanisms remain unclear, although a high number of neutrophils in the lungs of COPD patients is known to correlate with poor prognosis. Interleukin (IL)-22 is a cytokine that plays a pivotal role in lung antimicrobial defence and tissue protection. We hypothesised that neutrophils secrete proteases that may have adverse effects in COPD, by altering the IL-22 receptor (IL-22R)-dependent signalling.Using in vitro and in vivo approaches as well as reverse transcriptase quantitative PCR, flow cytometry and/or Western blotting techniques, we first showed that pathogens such as the influenza virus promote IL-22R expression in human bronchial epithelial cells, whereas Pseudomonas aeruginosa, bacterial lipopolysaccharide or cigarette smoke do not. Most importantly, neutrophil proteases cleave IL-22R and impair IL-22-dependent immune signalling and expression of antimicrobial effectors such as β-defensin-2. This proteolysis resulted in the release of a soluble fragment of IL-22R, which was detectable both in cellular and animal models as well as in sputa from COPD patients with acute exacerbations.Hence, our study reveals an unsuspected regulation by the proteolytic action of neutrophil enzymes of IL-22-dependent lung host response. This process probably enhances pathogen replication, and ultimately COPD exacerbations.
authors.affiliation: INSERM, Centre d'Etude des Pathologies Respiratoires, U1100, Tours, France Université François Rabelais de Tours, Tours, France Service de Réanimation Polyvalente, Centre Hospitalier Régional Universitaire de Tours, Tours, France.
authors.forename: Antoine
authors.initials: A
authors.lastname: Guillon
authors.affiliation: INSERM, Centre d'Etude des Pathologies Respiratoires, U1100, Tours, France Université François Rabelais de Tours, Tours, France Service de Réanimation Polyvalente, Centre Hospitalier Régional Universitaire de Tours, Tours, France.
authors.forename: Youenn
authors.initials: Y
authors.lastname: Jouan
authors.affiliation: INSERM, Centre d'Etude des Pathologies Respiratoires, U1100, Tours, France Université François Rabelais de Tours, Tours, France.
authors.forename: Deborah
authors.initials: D
authors.lastname: Brea
authors.affiliation: INSERM, Centre d'Etude des Pathologies Respiratoires, U1100, Tours, France Université François Rabelais de Tours, Tours, France.
authors.forename: Fabien
authors.initials: F
authors.lastname: Gueugnon
authors.affiliation: INSERM, Centre d'Etude des Pathologies Respiratoires, U1100, Tours, France Université François Rabelais de Tours, Tours, France.
authors.forename: Emilie
authors.initials: E
authors.lastname: Dalloneau
authors.affiliation: INSERM, Centre d'Etude des Pathologies Respiratoires, U1100, Tours, France Université François Rabelais de Tours, Tours, France.
authors.forename: Thomas
authors.initials: T
authors.lastname: Baranek
authors.affiliation: INSERM, Centre d'Etude des Pathologies Respiratoires, U1100, Tours, France Université François Rabelais de Tours, Tours, France.
authors.forename: Clémence
authors.identifier: http://orcid.org/0000-0001-7080-5080
authors.initials: C
authors.lastname: Henry
authors.affiliation: INSERM, Centre d'Etude des Pathologies Respiratoires, U1100, Tours, France Université François Rabelais de Tours, Tours, France.
authors.forename: Eric
authors.initials: E
authors.lastname: Morello
authors.affiliation: Ludwig Institute for Cancer Research, Brussels, Belgium De Duve Institute, Universite Catholique de Louvain, Brussels, Belgium.
authors.forename: Jean-Christophe
authors.initials: JC
authors.lastname: Renauld
authors.affiliation: Université Lille Nord de France, Lille, France Lille Centre for Infection and Immunity, Institut Pasteur de Lille, Lille, France Unité Mixte de Recherche 8204, Centre National de la Recherche Scientifique, Lille, France INSERM, U1019, Team 8, Lille, France.
authors.forename: Muriel
authors.initials: M
authors.lastname: Pichavant
authors.affiliation: Université Lille Nord de France, Lille, France Lille Centre for Infection and Immunity, Institut Pasteur de Lille, Lille, France Unité Mixte de Recherche 8204, Centre National de la Recherche Scientifique, Lille, France INSERM, U1019, Team 8, Lille, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Gosset
authors.affiliation: INSERM, Centre d'Etude des Pathologies Respiratoires, U1100, Tours, France Université François Rabelais de Tours, Tours, France.
authors.forename: Yves
authors.initials: Y
authors.lastname: Courty
authors.affiliation: INSERM, Centre d'Etude des Pathologies Respiratoires, U1100, Tours, France Université François Rabelais de Tours, Tours, France.
authors.forename: Patrice
authors.initials: P
authors.lastname: Diot
authors.affiliation: INSERM, Centre d'Etude des Pathologies Respiratoires, U1100, Tours, France Université François Rabelais de Tours, Tours, France si-tahar@univ-tours.fr.
authors.forename: Mustapha
authors.initials: M
authors.lastname: Si-Tahar
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D015153:Blotting, Western; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004847:Epithelial Cells / Q000201:enzymology* / Q000382:microbiology; D006801:Humans; D007113:Immunity, Innate / Q000187:drug effects* / Q000502:physiology; D051379:Mice; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism*; D010447:Peptide Hydrolases / Q000378:metabolism; D011550:Pseudomonas aeruginosa / Q000187:drug effects / Q000472:pathogenicity; D029424:Pulmonary Disease, Chronic Obstructive / Q000188:drug therapy / Q000276:immunology / Q000382:microbiology*; D060888:Real-Time Polymerase Chain Reaction; D018123:Receptors, Interleukin / Q000276:immunology / Q000378:metabolism*; D012494:Sampling Studies; D012680:Sensitivity and Specificity; D012907:Smoking / Q000009:adverse effects; D018709:Statistics, Nonparametric; D023083:beta-Defensins / Q000494:pharmacology
chemical_list: D015415:Biomarkers; D018123:Receptors, Interleukin; D023083:beta-Defensins; C415369:interleukin-22 receptor; D010447:Peptide Hydrolases