Regulation of the inflammasome by ceramide in cystic fibrosis lungs

Cell Physiol Biochem. 2014;34(1):45-55. doi: 10.1159/000362983. Epub 2014 Jun 16.


Background: Cystic fibrosis (CF), the most common autosomal recessive disorder in Western countries, is characterized by chronic pulmonary inflammation, reduced mucociliary clearance, and increased susceptibility to infection. Our studies using Cftr-deficient mice and human CF specimens showed that ceramide accumulates in CF lungs and mediates increased cell death, susceptibility to infections, and inflammation.

Methods: We used Cftr-deficient and syngenic wildtype mice as well as Cftr-deficient mice heterozygous for the acid sphingomyelinase. We determined activation and topology of inflammasome components as well as expression of tight junction proteins by confocal microscopy, western blotting and ELISA.

Results: We demonstrate an upregulation and membrane recruitment of the adapter protein apoptosis-associated speck-like protein (Asc), a major component of the inflammasome, and caspase 1, an activation of Jun N-terminal kinase as well as an altered distribution and a degradation of the tight junction proteins ZO-1, ZO-2 and Occludin in lungs of CF mice. All of these events are abrogated in CF mice that are heterozygous for the acid sphingomyelinase and, therefore, show normal levels of ceramide in their lungs. These alterations indicate an activation of the inflammasome by ceramide in the lungs of CF mice. Consistent with this notion, we observe a normalization of the increased levels of the cytokines IL-1β and KC/IL-8 in lungs of CF mice upon treatment with caspase 1 inhibitors.

Conclusion: Our data suggest a signaling cascade from ceramide via the inflammasome to caspase 1, the release of cytokines and an alteration of tight junction proteins in CF epithelia.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis Regulatory Proteins / metabolism
  • Caspase 1 / chemistry
  • Caspase 1 / metabolism
  • Ceramides / metabolism*
  • Cystic Fibrosis / metabolism
  • Cystic Fibrosis / pathology
  • Cystic Fibrosis Transmembrane Conductance Regulator / deficiency
  • Cystic Fibrosis Transmembrane Conductance Regulator / genetics
  • Cystic Fibrosis Transmembrane Conductance Regulator / metabolism
  • Disease Models, Animal
  • Humans
  • Inflammasomes / metabolism*
  • Interleukin-1beta / metabolism
  • Interleukin-8 / metabolism
  • JNK Mitogen-Activated Protein Kinases / metabolism
  • Lung / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Inbred CFTR
  • Sphingomyelin Phosphodiesterase / deficiency
  • Sphingomyelin Phosphodiesterase / genetics
  • Sphingomyelin Phosphodiesterase / metabolism
  • Zonula Occludens-1 Protein / metabolism
  • Zonula Occludens-2 Protein / metabolism


  • Apoptosis Regulatory Proteins
  • Ceramides
  • Inflammasomes
  • Interleukin-1beta
  • Interleukin-8
  • Tjp1 protein, mouse
  • Tjp2 protein, mouse
  • Zonula Occludens-1 Protein
  • Zonula Occludens-2 Protein
  • Cystic Fibrosis Transmembrane Conductance Regulator
  • JNK Mitogen-Activated Protein Kinases
  • acid sphingomyelinase-1
  • ASMase, mouse
  • Sphingomyelin Phosphodiesterase
  • Caspase 1