title: IL-1 receptor antagonist ameliorates inflammasome-dependent inflammation in murine and human cystic fibrosis.
abstract: Dysregulated inflammasome activation contributes to respiratory infections and pathologic airway inflammation. Through basic and translational approaches involving murine models and human genetic epidemiology, we show here the importance of the different inflammasomes in regulating inflammatory responses in mice and humans with cystic fibrosis (CF), a life-threatening disorder of the lungs and digestive system. While both contributing to pathogen clearance, NLRP3 more than NLRC4 contributes to deleterious inflammatory responses in CF and correlates with defective NLRC4-dependent IL-1Ra production. Disease susceptibility in mice and microbial colonization in humans occurs in conditions of genetic deficiency of NLRC4 or IL-1Ra and can be rescued by administration of the recombinant IL-1Ra, anakinra. These results indicate that pathogenic NLRP3 activity in CF could be negatively regulated by IL-1Ra and provide a proof-of-concept evidence that inflammasomes are potential targets to limit the pathological consequences of microbial colonization in CF.
authors.affiliation: Department of Experimental Medicine, University of Perugia, 06132 Perugia, Italy.
authors.forename: Rossana G
authors.initials: RG
authors.lastname: Iannitti
authors.affiliation: Department of Experimental Medicine, University of Perugia, 06132 Perugia, Italy.
authors.forename: Valerio
authors.initials: V
authors.lastname: Napolioni
authors.affiliation: Department of Experimental Medicine, University of Perugia, 06132 Perugia, Italy.
authors.forename: Vasilis
authors.initials: V
authors.lastname: Oikonomou
authors.affiliation: Department of Experimental Medicine, University of Perugia, 06132 Perugia, Italy.
authors.forename: Antonella
authors.initials: A
authors.lastname: De Luca
authors.affiliation: Department of Experimental Medicine, University of Perugia, 06132 Perugia, Italy.
authors.forename: Claudia
authors.initials: C
authors.lastname: Galosi
authors.affiliation: Department of Experimental Medicine, University of Perugia, 06132 Perugia, Italy.
authors.forename: Marilena
authors.initials: M
authors.lastname: Pariano
authors.affiliation: Department of Experimental Medicine, University of Perugia, 06132 Perugia, Italy.
authors.forename: Cristina
authors.initials: C
authors.lastname: Massi-Benedetti
authors.affiliation: Department of Experimental Medicine, University of Perugia, 06132 Perugia, Italy.
authors.forename: Monica
authors.initials: M
authors.lastname: Borghi
authors.affiliation: Department of Experimental Medicine, University of Perugia, 06132 Perugia, Italy.
authors.forename: Matteo
authors.initials: M
authors.lastname: Puccetti
authors.affiliation: Unit of Endocrinology and Diabetes, Bambino Gesù Children's Hospital, 00165 Rome, Italy.
authors.forename: Vincenzina
authors.initials: V
authors.lastname: Lucidi
authors.affiliation: Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, University of Milan, 20122 Milan, Italy.
authors.forename: Carla
authors.initials: C
authors.lastname: Colombo
authors.affiliation: Children's Hospital Bambino Gesù IRCCS, 00165 Rome, Italy.
authors.forename: Ersilia
authors.initials: E
authors.lastname: Fiscarelli
authors.affiliation: Division of Hygiene and Medical Microbiology, Innsbruck Medical University, 6020 Innsbruck, Austria.
authors.forename: Cornelia
authors.initials: C
authors.lastname: Lass-Flörl
authors.affiliation: Unit of Endocrinology and Diabetes, Bambino Gesù Children's Hospital, 00165 Rome, Italy.
authors.forename: Fabio
authors.initials: F
authors.lastname: Majo
authors.affiliation: Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, University of Milan, 20122 Milan, Italy.
authors.forename: Lisa
authors.initials: L
authors.lastname: Cariani
authors.affiliation: Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, University of Milan, 20122 Milan, Italy.
authors.forename: Maria
authors.initials: M
authors.lastname: Russo
authors.affiliation: Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, University of Milan, 20122 Milan, Italy.
authors.forename: Luigi
authors.initials: L
authors.lastname: Porcaro
authors.affiliation: Children's Hospital Bambino Gesù IRCCS, 00165 Rome, Italy.
authors.forename: Gabriella
authors.initials: G
authors.lastname: Ricciotti
authors.affiliation: CF Centre, Medical University Innsbruck, 6020 Innsbruck, Austria.
authors.forename: Helmut
authors.initials: H
authors.lastname: Ellemunter
authors.affiliation: Servizio di Supporto Fibrosi Cistica, Istituto Ospedale G. Tatarella, Foggia, 71042 Cerignola, Italy.
authors.forename: Luigi
authors.initials: L
authors.lastname: Ratclif
authors.affiliation: Department of Mother and Child Health, Salesi Children's Hospital, 60128 Ancona, Italy.
authors.forename: Fernando Maria
authors.initials: FM
authors.lastname: De Benedictis
authors.affiliation: Department of Experimental Medicine, University of Perugia, 06132 Perugia, Italy.
authors.forename: Vincenzo Nicola
authors.initials: VN
authors.lastname: Talesa
authors.affiliation: Radboud Center for Infectious Diseases, Nijmegen, 6500 HB, The Netherlands.|Division of Infectious Diseases, University of Colorado Denver, Aurora, Colorado 80045, USA.
authors.forename: Charles A
authors.initials: CA
authors.lastname: Dinarello
authors.affiliation: Division of Infectious Diseases, University of Colorado Denver, Aurora, Colorado 80045, USA.|Department of Internal Medicine, Radboud Center for Infectious diseases (RCI), Radboudumc, Nijmegen, 6500 HB, The Netherlands.
authors.forename: Frank L
authors.initials: FL
authors.lastname: van de Veerdonk
authors.affiliation: Department of Experimental Medicine, University of Perugia, 06132 Perugia, Italy.
authors.forename: Luigina
authors.initials: L
authors.lastname: Romani
mesh_terms: D000293:Adolescent; D000328:Adult; D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000276:immunology; D001228:Aspergillosis / Q000276:immunology*; D001232:Aspergillus fumigatus; D001343:Autophagy / Q000235:genetics / Q000276:immunology; D015153:Blotting, Western; D053468:CARD Signaling Adaptor Proteins / Q000235:genetics / Q000276:immunology; D002135:Calcium-Binding Proteins / Q000235:genetics / Q000276:immunology; D002352:Carrier Proteins / Q000235:genetics / Q000276:immunology; D002460:Cell Line; D002648:Child; D002675:Child, Preschool; D003550:Cystic Fibrosis / Q000235:genetics / Q000276:immunology* / Q000382:microbiology; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics; D016207:Cytokines / Q000235:genetics* / Q000276:immunology; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D004847:Epithelial Cells / Q000276:immunology*; D005260:Female; D005455:Fluorescent Antibody Technique; D006801:Humans; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D007223:Infant; D058847:Inflammasomes / Q000235:genetics* / Q000276:immunology; D007249:Inflammation; D053590:Interleukin 1 Receptor Antagonist Protein / Q000235:genetics* / Q000276:immunology / Q000494:pharmacology; D008168:Lung / Q000378:metabolism*; D008264:Macrophages / Q000276:immunology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008875:Middle Aged; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D020641:Polymorphism, Single Nucleotide; D011552:Pseudomonas Infections / Q000276:immunology*; D011550:Pseudomonas aeruginosa; D020545:Respiratory Mucosa / Q000166:cytology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D055815:Young Adult
chemical_list: D051017:Apoptosis Regulatory Proteins; D053468:CARD Signaling Adaptor Proteins; C505032:CFTR protein, human; D002135:Calcium-Binding Proteins; D002352:Carrier Proteins; D016207:Cytokines; C507763:IL1RN protein, human; C507764:Il1rn protein, mouse; D058847:Inflammasomes; D053590:Interleukin 1 Receptor Antagonist Protein; C512299:Ipaf protein, mouse; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C435692:NLRC4 protein, human; C453881:NLRP3 protein, human; C492716:Nlrp3 protein, mouse; D019005:Cystic Fibrosis Transmembrane Conductance Regulator