title: IL-17A impairs host tolerance during airway chronic infection by Pseudomonas aeruginosa.
abstract: Resistance and tolerance mechanisms participate to the interplay between host and pathogens. IL-17-mediated response has been shown to be crucial for host resistance to respiratory infections, whereas its role in host tolerance during chronic airway colonization is still unclear. Here, we investigated whether IL-17-mediated response modulates mechanisms of host tolerance during airways chronic infection by P. aeruginosa. First, we found that IL-17A levels were sustained in mice at both early and advanced stages of P. aeruginosa chronic infection and confirmed these observations in human respiratory samples from cystic fibrosis patients infected by P. aeruginosa. Using IL-17a(-/-) or IL-17ra(-/-) mice, we found that the deficiency of IL-17A/IL-17RA axis was associated with: i) increased incidence of chronic infection and bacterial burden, indicating its role in the host resistance to P. aeruginosa; ii) reduced cytokine levels (KC), tissue innate immune cells and markers of tissue damage (pro-MMP-9, elastin degradation, TGF-β1), proving alteration of host tolerance. Blockade of IL-17A activity by a monoclonal antibody, started when chronic infection is established, did not alter host resistance but increased tolerance. In conclusion, this study identifies IL-17-mediated response as a negative regulator of host tolerance during P. aeruginosa chronic airway infection.
authors.affiliation: Infections and Cystic Fibrosis Unit, Division of Immunology, Transplantation and Infectious Diseases, IRCCS San Raffaele Scientific Institute, Milano, Italy.
authors.forename: Nicola Ivan
authors.initials: NI
authors.lastname: Lorè
authors.affiliation: Infections and Cystic Fibrosis Unit, Division of Immunology, Transplantation and Infectious Diseases, IRCCS San Raffaele Scientific Institute, Milano, Italy.
authors.forename: Cristina
authors.initials: C
authors.lastname: Cigana
authors.affiliation: Infections and Cystic Fibrosis Unit, Division of Immunology, Transplantation and Infectious Diseases, IRCCS San Raffaele Scientific Institute, Milano, Italy.
authors.forename: Camilla
authors.initials: C
authors.lastname: Riva
authors.affiliation: Infections and Cystic Fibrosis Unit, Division of Immunology, Transplantation and Infectious Diseases, IRCCS San Raffaele Scientific Institute, Milano, Italy.
authors.forename: Ida
authors.initials: I
authors.lastname: De Fino
authors.affiliation: University Center for Statistics in the Biomedical Sciences (CUSSB), Vita-Salute San Raffaele University, Milano, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Nonis
authors.affiliation: Infections and Cystic Fibrosis Unit, Division of Immunology, Transplantation and Infectious Diseases, IRCCS San Raffaele Scientific Institute, Milano, Italy.
authors.forename: Lorenza
authors.initials: L
authors.lastname: Spagnuolo
authors.affiliation: Infections and Cystic Fibrosis Unit, Division of Immunology, Transplantation and Infectious Diseases, IRCCS San Raffaele Scientific Institute, Milano, Italy.
authors.forename: Barbara
authors.initials: B
authors.lastname: Sipione
authors.affiliation: Cystic Fibrosis Microbiology Laboratory, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Milano, Italy.
authors.forename: Lisa
authors.initials: L
authors.lastname: Cariani
authors.affiliation: Cystic Fibrosis Microbiology Laboratory, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Milano, Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Girelli
authors.affiliation: School of Biosciences and Veterinary Medicine, University of Camerino, Italy.
authors.forename: Giacomo
authors.initials: G
authors.lastname: Rossi
authors.affiliation: Lymphocytes Activation Unit, Division of Immunology, Transplantation and Infectious Diseases, IRCCS San Raffaele Scientific Institute, Milano, Italy.
authors.forename: Veronica
authors.initials: V
authors.lastname: Basso
authors.affiliation: Cystic Fibrosis Center, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Milano, Italy.
authors.forename: Carla
authors.initials: C
authors.lastname: Colombo
authors.affiliation: Lymphocytes Activation Unit, Division of Immunology, Transplantation and Infectious Diseases, IRCCS San Raffaele Scientific Institute, Milano, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Mondino
authors.affiliation: Infections and Cystic Fibrosis Unit, Division of Immunology, Transplantation and Infectious Diseases, IRCCS San Raffaele Scientific Institute, Milano, Italy.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Bragonzi
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D003550:Cystic Fibrosis / Q000382:microbiology*; D004195:Disease Models, Animal; D055785:Gene Knockdown Techniques; D006801:Humans; D007113:Immunity, Innate; D015994:Incidence; D020381:Interleukin-17 / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D011552:Pseudomonas Infections / Q000235:genetics / Q000276:immunology* / Q000382:microbiology; D011550:Pseudomonas aeruginosa / Q000276:immunology / Q000472:pathogenicity*; D012141:Respiratory Tract Infections / Q000235:genetics / Q000276:immunology / Q000382:microbiology*; D015854:Up-Regulation
chemical_list: D015415:Biomarkers; C508717:IL17A protein, human; D020381:Interleukin-17