IL-1 receptor antagonist ameliorates inflammasome-dependent inflammation in murine and human cystic fibrosis

Rossana G. Iannitti, Valerio Napolioni, Vasilis Oikonomou, Antonella De Luca, Claudia Galosi, Marilena Pariano, Cristina Massi-Benedetti, Monica Borghi, Matteo Puccetti, Vincenzina Lucidi, Carla Colombo, Ersilia Fiscarelli, Cornelia Lass-Flörl, Fabio Majo, Lisa Cariani, Maria Russo, Luigi Porcaro, Gabriella Ricciotti, Helmut Ellemunter, Luigi Ratclif, Fernando Maria De Benedictis, Vincenzo Nicola Talesa, Charles A. Dinarello, Frank L. van de Veerdonk and Luigina Romani ()
Additional contact information
Rossana G. Iannitti: University of Perugia
Valerio Napolioni: University of Perugia
Vasilis Oikonomou: University of Perugia
Antonella De Luca: University of Perugia
Claudia Galosi: University of Perugia
Marilena Pariano: University of Perugia
Cristina Massi-Benedetti: University of Perugia
Monica Borghi: University of Perugia
Matteo Puccetti: University of Perugia
Vincenzina Lucidi: Unit of Endocrinology and Diabetes, Bambino Gesù Children's Hospital
Carla Colombo: Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, University of Milan
Ersilia Fiscarelli: Children's Hospital Bambino Gesù IRCCS
Cornelia Lass-Flörl: Innsbruck Medical University
Fabio Majo: Unit of Endocrinology and Diabetes, Bambino Gesù Children's Hospital
Lisa Cariani: Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, University of Milan
Maria Russo: Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, University of Milan
Luigi Porcaro: Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, University of Milan
Gabriella Ricciotti: Children's Hospital Bambino Gesù IRCCS
Helmut Ellemunter: CF Centre, Medical University Innsbruck
Luigi Ratclif: Servizio di Supporto Fibrosi Cistica, Istituto Ospedale G. Tatarella
Fernando Maria De Benedictis: Salesi Children’s Hospital
Vincenzo Nicola Talesa: University of Perugia
Charles A. Dinarello: Radboud Center for Infectious Diseases
Frank L. van de Veerdonk: University of Colorado Denver
Luigina Romani: University of Perugia

Nature Communications, 2016, vol. 7, issue 1, 1-16

Abstract: 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 occurrs 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.

Date: 2016
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DOI: 10.1038/ncomms10791

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