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

Nat Commun. 2016 Mar 14;7:10791. doi: 10.1038/ncomms10791.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Animals
  • Apoptosis Regulatory Proteins / genetics
  • Apoptosis Regulatory Proteins / immunology
  • Aspergillosis / immunology*
  • Aspergillus fumigatus
  • Autophagy / genetics
  • Autophagy / immunology
  • Blotting, Western
  • CARD Signaling Adaptor Proteins / genetics
  • CARD Signaling Adaptor Proteins / immunology
  • Calcium-Binding Proteins / genetics
  • Calcium-Binding Proteins / immunology
  • Carrier Proteins / genetics
  • Carrier Proteins / immunology
  • Cell Line
  • Child
  • Child, Preschool
  • Cystic Fibrosis / genetics
  • Cystic Fibrosis / immunology*
  • Cystic Fibrosis / microbiology
  • Cystic Fibrosis Transmembrane Conductance Regulator / genetics
  • Cytokines / genetics*
  • Cytokines / immunology
  • Disease Models, Animal
  • Enzyme-Linked Immunosorbent Assay
  • Epithelial Cells / immunology*
  • Female
  • Fluorescent Antibody Technique
  • 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
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • Polymorphism, Single Nucleotide
  • Pseudomonas Infections / immunology*
  • Pseudomonas aeruginosa
  • Respiratory Mucosa / cytology
  • Reverse Transcriptase Polymerase Chain Reaction
  • Young Adult

Substances

  • Apoptosis Regulatory Proteins
  • CARD Signaling Adaptor Proteins
  • CFTR protein, human
  • Calcium-Binding Proteins
  • Carrier Proteins
  • Cytokines
  • IL1RN protein, human
  • Il1rn protein, mouse
  • Inflammasomes
  • Interleukin 1 Receptor Antagonist Protein
  • Ipaf protein, mouse
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • NLRC4 protein, human
  • NLRP3 protein, human
  • Nlrp3 protein, mouse
  • Cystic Fibrosis Transmembrane Conductance Regulator