Journal Article

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

Romani, Luigina, Borghi, Monica, Fiscarelli, Ersilia, Majo, Fabio, Cariani, Lisa, Colombo, Carla, Iannitti, Rossana G., De Benedictis, Fernando Maria, Lucidi, Vincenzina, Ratclif, Luigi, Oikonomou, Vasilis, Massi-Benedetti, Cristina, Napolioni, Valerio, Ellemunter, Helmut, Galosi, Claudia, Ricciotti, Gabriella, Porcaro, Luigi, Dinarello, Charles A., Puccetti, Matteo, Talesa, Vincenzo Nicola, van de Veerdonk, Frank L., Russo, Maria, Lass-Flörl, Cornelia, Pariano, Marilena, De Luca, Antonella

2016

Overview

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. IL-1-mediated inflammation contributes to the pathogenesis of cystic fibrosis. Here the authors show that this is largely due to NLRP3 activation, whereas NLRP4 induces IL-1Ra, limiting the overall inflammasome activity and providing a therapeutic angle to ameliorate the disease.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 13/1 / 13/106 / 13/21 / 13/51 / 13/89 / 14/1 / 14/34 / 14/63 / 38/1 / 38/77 / 38/89 / 38/90 / 631/250/256/2177 / 631/92/436/108 / 64/60 / 692/308 / 692/699/1785 / 82/1 / 82/29 / 82/51 / 82/80 / Adolescent / Adult / Animals / Apoptosis Regulatory Proteins - genetics / Apoptosis Regulatory Proteins - immunology / Aspergillosis - immunology / Aspergillus fumigatus / Autophagy - genetics / Autophagy - immunology / Blotting, Western / Calcium-Binding Proteins - genetics / Calcium-Binding Proteins - immunology / CARD Signaling Adaptor Proteins - genetics / CARD Signaling Adaptor Proteins - immunology / Carrier Proteins - genetics / Carrier Proteins - immunology / Cell Line / Child / Child, Preschool / Colonization / Cystic Fibrosis - genetics / Cystic Fibrosis - immunology / Cystic Fibrosis - microbiology / Cystic Fibrosis Transmembrane Conductance Regulator - genetics / Cytokines - genetics / Cytokines - immunology / Digestive system / Disease Models, Animal / Enzyme-Linked Immunosorbent Assay / Epidemiology / Epithelial Cells - immunology / Female / Fluorescent Antibody Technique / Humanities and Social Sciences / Humans / Immunohistochemistry / In Situ Nick-End Labeling / Infant / Inflammasomes - genetics / Inflammasomes - immunology / Inflammation / Interleukin 1 Receptor Antagonist Protein - genetics / Interleukin 1 Receptor Antagonist Protein - immunology / Interleukin 1 Receptor Antagonist Protein - pharmacology / Lung - metabolism / Macrophages - immunology / Male / Mice / Mice, Inbred C57BL / Mice, Knockout / Middle Aged / multidisciplinary / NLR Family, Pyrin Domain-Containing 3 Protein / Polymorphism, Single Nucleotide / Pseudomonas aeruginosa / Pseudomonas Infections - immunology / Respiratory Mucosa - cytology / Reverse Transcriptase Polymerase Chain Reaction / Science / Science (multidisciplinary) / Young Adult