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

doi:10.1016/j.chom.2017.05.001

Abstract

SummaryChronic 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.

Highlights

Cystic fibrosis (CF) is the most common autosomal recessive disorder in the European Union (EU) and the United States (USA), affecting one of every 2,500 children born in Western countries
We observed that b1-integrins accumulate on the luminal membrane of upperairway epithelial cells from mice and humans with cystic fibrosis (CF). b1-integrin accumulation is due to increased ceramide and the formation of ceramide platforms that trap b1-integrins on the luminal pole of bronchial epithelial cells. b1-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 b1-integrin internalization via anti-b1-integrin antibodies or the RGD peptide ligand—or by genetic or pharmacological correction of ceramide levels—normalizes b1-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

Summary

Introduction

Cystic fibrosis (CF) is the most common autosomal recessive disorder in the European Union (EU) and the United States (USA), affecting one of every 2,500 children born in Western countries. It is caused by mutations of the CF transmembrane conductance regulator gene (human: CFTR, mouse: Cftr). 80% of CF patients will host P. aeruginosa by the age of 25 (CF foundation, 2010). In addition to their increased susceptibility to P. aeruginosa, CF lungs are characterized by chronic inflammation and progressive fibrosis (Elborn, 2016). The molecular mechanisms that mediate all three hallmarks of the disease—i.e., infection, inflammation, and fibrosis—require further definition

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