Pseudomonas aeruginosa elastase disables proteinase-activated receptor 2 in respiratory epithelial cells

Sophie Dulon, Dominique Leduc, Graeme S. Cottrell, Jacques D'Alayer, Kristina K. Hansen, Nigel W. Bunnett, Morley D. Hollenberg, Dominique Pidard, Michel Chignard

Research output: Contribution to journalArticlepeer-review

Abstract

Pseudomonas aeruginosa, a major lung pathogen in cystic fibrosis (CF) patients, secretes an elastolytic metalloproteinase (EPa) contributing to bacterial pathogenicity. Proteinase-activated receptor 2 (PAR2), implicated in the pulmonary innate defense, is activated by the cleavage of its extracellular N-terminal domain, unmasking a new N-terminal sequence starting with SLIGKV, which binds intramolecularly and activates PAR2. We show that EPa cleaves the N-terminal domain of PAR2 from the cell surface without triggering receptor endocytosis as trypsin does. As evaluated by measurements of cytosolic calcium as well as prostaglandin E2 and interleukin-8 production, this cleavage does not activate PAR2, but rather disarms the receptor for subsequent activation by trypsin, but not by the synthetic receptor-activating peptide, SLIGKV-NH2. Proteolysis by EPa of synthetic peptides representing the N-terminal cleavage/activation sequences of either human or rat PAR2 indicates that cleavages resulting from EPa activity would not produce receptor-activating tethered ligands, but would disarm PAR2 in regard to any further activating proteolysis by activating proteinases. Our data indicate that a pathogen-derived proteinase like EPa can potentially silence the function of PAR2 in the respiratory tract, thereby altering the host innate defense mechanisms and respiratory functions, and thus contributing to pathogenesis in the setting of a disease like CF.

Original languageEnglish (US)
Pages (from-to)411-419
Number of pages9
JournalAmerican Journal of Respiratory Cell and Molecular Biology
Volume32
Issue number5
DOIs
StatePublished - May 2005

Keywords

  • Cystic fibrosis
  • Infection
  • Inflammation
  • Lung
  • Protease

ASJC Scopus subject areas

  • Molecular Biology
  • Pulmonary and Respiratory Medicine
  • Clinical Biochemistry
  • Cell Biology

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