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

Nature Medicine volume 14, pages 382–391 (2008)Cite this article

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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Author notes

  1. Volker Teichgräber, Martina Ulrich, Gerd Döring and Erich Gulbins: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Molecular Biology, Hufelandstrasse 55, University of Duisburg-Essen, Essen, 45122, Germany

    Volker Teichgräber, Barbara Wilker, Heike Grassme & Erich Gulbins

  2. Institute of Medical Microbiology and Hygiene, Wilhelmstrasse 31, Tübingen, 72074, Germany

    Martina Ulrich, Cheyla Conceição De Oliveira–Munding & Gerd Döring

  3. Department of Anatomy, Friedrich-Loeffler-Strasse 23c, University of Greifswald, Greifswald, 17487, Germany

    Nicole Endlich

  4. Children`s Clinic, Auf dem Schnarrenberg, University of Tübingen, Tübingen, 72076, Germany

    Joachim Riethmüller

  5. Case Western Reserve University, Biomedical Research Building 827, 10900 Euclid Avenue, Cleveland, 44106–4948, Ohio, USA

    Anna M van Heeckeren

  6. Department of Cardiothoracic Surgery, University of Southern California, 1520 San Pablo Street, Suite 4300, Los Angeles, 90033, California, USA

    Mark L Barr

  7. Department of Neurology, Auf dem Schnarrenberg, University of Tübingen, Tübingen, 72076, Germany

    Gabriele von Kürthy & Michael Weller

  8. Department of Pathology and Neuropathology, Hufelandstrasse 55, University of Duisburg-Essen, Essen, 45122, Germany

    Kurt W Schmid

  9. Medical University School, Carl-Neuberg-Strasse, Hannover, 30625, Germany

    Burkhard Tümmler

  10. Department of Physiology, Gmelinstrasse 5, University of Tübingen, Tübingen, 72076, Germany

    Florian Lang

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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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