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Ceramide accumulation mediates inflammation, cell death and infection susceptibility in cystic fibrosis

Abstract

Microbial lung infections are the major cause of morbidity and mortality in the hereditary metabolic disorder cystic fibrosis, yet the molecular mechanisms leading from the mutation of cystic fibrosis transmembrane conductance regulator (CFTR) to lung infection are still unclear. Here, we show that ceramide age-dependently accumulates in the respiratory tract of uninfected Cftr-deficient mice owing to an alkalinization of intracellular vesicles in Cftr-deficient cells. This change in pH results in an imbalance between acid sphingomyelinase (Asm) cleavage of sphingomyelin to ceramide and acid ceramidase consumption of ceramide, resulting in the higher levels of ceramide. The accumulation of ceramide causes Cftr-deficient mice to suffer from constitutive age-dependent pulmonary inflammation, death of respiratory epithelial cells, deposits of DNA in bronchi and high susceptibility to severe Pseudomonas aeruginosa infections. Partial genetic deficiency of Asm in Cftr−/−Smpd1+/− mice or pharmacological treatment of Cftr-deficient mice with the Asm blocker amitriptyline normalizes pulmonary ceramide and prevents all pathological findings, including susceptibility to infection. These data suggest inhibition of Asm as a new treatment strategy for cystic fibrosis.

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Figure 1: Cftr deficiency results in pulmonary ceramide accumulation.
Figure 2: Influence of vesicular pH on ceramide levels.
Figure 3: Ceramide accumulation mediates hypersusceptibility of Cftr-deficient mice to P.aeruginosa infection.
Figure 4: Cftr-deficient mice suffer from constitutive pulmonary inflammation corrected by normalization of pulmonary ceramide levels.
Figure 5: Pulmonary ceramide accumulation results in constitutive increase of respiratory cell death and deposition of DNA on the respiratory epithelium.
Figure 6: DNA deposits are crucial in determining the high susceptibility of Cftr-deficient mice to P.aeruginosa infection.

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Acknowledgements

We thank R. Ramphal (University of Florida) for providing P. aeruginosa PAK and PAK mutant strains, G.B. Pier (Channing Laboratory, Brigham and Women's Hospital, Harvard Medical School) for a P. aeruginosa–specific antibody and C. Meisner for statistical evaluations. We thank H. Wegner, M. Niemayer and S. Moyrer for excellent technical assistance. The study was supported by the Deutsche Forschungsgemeinschaft grants Gu 335/10–3/4 and Gu 335/16–1 and the Mukoviszidose e.V. grant F01/04 to E.G.

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Correspondence to Erich Gulbins.

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Teichgräber, V., Ulrich, M., Endlich, N. et al. Ceramide accumulation mediates inflammation, cell death and infection susceptibility in cystic fibrosis. Nat Med 14, 382–391 (2008). https://doi.org/10.1038/nm1748

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