β1-Integrin Accumulates in Cystic Fibrosis Luminal Airway Epithelial Membranes and Decreases Sphingosine, Promoting Bacterial Infections

Heike Grassmé, Brian Henry, Regan Ziobro, Katrin Anne Becker, Joachim Riethmüller, Aaron Gardner, Aaron P. Seitz, Joerg Steinmann, Stephan Lang, Christopher Ward, Edward H. Schuchman, Charles C. Caldwell, Markus Kamler, Michael J. Edwards, Malcolm Brodlie, Erich Gulbins

Research output: Contribution to journalArticlepeer-review

77 Scopus citations

Abstract

Chronic pulmonary colonization with bacterial pathogens, particularly Pseudomonas aeruginosa, is the primary cause of morbidity and mortality in patients with cystic fibrosis (CF). We observed that β1-integrins accumulate on the luminal membrane of upper-airway epithelial cells from mice and humans with CF. β1-integrin accumulation is due to increased ceramide and the formation of ceramide platforms that trap β1-integrins on the luminal pole of bronchial epithelial cells. β1-integrins downregulate acid ceramidase expression, resulting in further accumulation of ceramide and consequent reduction of surface sphingosine, a lipid that kills bacteria. Interrupting this vicious cycle by triggering surface β1-integrin internalization via anti-β1-integrin antibodies or the RGD peptide ligand—or by genetic or pharmacological correction of ceramide levels—normalizes β1-integrin distribution and sphingosine levels in CF epithelial cells and prevents P. aeruginosa infection in CF mice. These findings suggest a therapeutic avenue to ameliorate CF-associated bacterial infections.

Original languageEnglish
Pages (from-to)707-718.e8
JournalCell Host and Microbe
Volume21
Issue number6
DOIs
StatePublished - 14 Jun 2017

Keywords

  • Cystic fibrosis
  • Pseudomonas aeruginosa
  • acid ceramidase
  • ceramide
  • epithelial cells
  • integrin
  • membrane domains
  • pneumonia
  • receptor clustering
  • sphingosine

Fingerprint

Dive into the research topics of 'β1-Integrin Accumulates in Cystic Fibrosis Luminal Airway Epithelial Membranes and Decreases Sphingosine, Promoting Bacterial Infections'. Together they form a unique fingerprint.

Cite this