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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.

SUBMITTER: Iannitti RG

PROVIDER: S-EPMC4793079 | biostudies-literature | 2016 Mar

REPOSITORIES: biostudies-literature

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

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

Nature communications 20160314

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 d ...[more]

PMID: 26972847

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Project description:UnlabelledCystic fibrosis-associated liver disease is a chronic cholangiopathy that negatively affects the quality of life of cystic fibrosis patients. In addition to reducing biliary chloride and bicarbonate secretion, up-regulation of toll-like receptor 4/nuclear factor kappa light-chain-enhancer of activated B cells (NF-κB)-dependent immune mechanisms plays a major role in the pathogenesis of cystic fibrosis-associated liver disease and may represent a therapeutic target. Nuclear receptors are transcription factors that regulate several intracellular functions. Some nuclear receptors, including peroxisome proliferator-activated receptor-γ (PPAR-γ), may counterregulate inflammation in a tissue-specific manner. In this study, we explored the anti-inflammatory effect of PPAR-γ stimulation in vivo in cystic fibrosis transmembrane conductance regulator (Cftr) knockout mice exposed to dextran sodium sulfate and in vitro in primary cholangiocytes isolated from wild-type and from Cftr-knockout mice exposed to lipopolysaccharide. We found that in CFTR-defective biliary epithelium expression of PPAR-γ is increased but that this does not result in increased receptor activity because the availability of bioactive ligands is reduced. Exogenous administration of synthetic agonists of PPAR-γ (pioglitazone and rosiglitazone) up-regulates PPAR-γ-dependent genes, while inhibiting the activation of NF-κB and the secretion of proinflammatory cytokines (lipopolysaccharide-induced CXC chemokine, monocyte chemotactic protein-1, macrophage inflammatory protein-2, granulocyte colony-stimulating factor, keratinocyte chemoattractant) in response to lipopolysaccharide. PPAR-γ agonists modulate NF-κB-dependent inflammation by up-regulating nuclear factor of kappa light polypeptide gene enhancer in B cells inhibitor alpha, a negative regulator of NF-κB. Stimulation of PPAR-γ in vivo (rosiglitazone) significantly attenuates biliary damage and inflammation in Cftr-knockout mice exposed to a dextran sodium sulfate-induced portal endotoxemia.ConclusionThese studies unravel a novel function of PPAR-γ in controlling biliary epithelium inflammation and suggest that impaired activation of PPAR-γ contributes to the chronic inflammatory state of CFTR-defective cholangiocytes.

Dataset Information

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

Publications

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

Similar Datasets

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