LL-37 complexation with glycosaminoglycans in cystic fibrosis lungs inhibits antimicrobial activity, which can be restored by hypertonic saline.
Bergsson, Gudmundur Reeves, Emer P McNally, Paul Chotirmall, Sanjay H Greene, Catherine M Greally, Peter Murphy, Philip O'Neill, Shane J McElvaney, Noel G
Bergsson, Gudmundur
Reeves, Emer P
McNally, Paul
Chotirmall, Sanjay H
Greene, Catherine M
Greally, Peter
Murphy, Philip
O'Neill, Shane J
McElvaney, Noel G
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Advisors
Editors
Other Contributors
Date
2009-07-01
Date Submitted
Keywords
Other Subjects
Subject Mesh
Adjuvants, Immunologic
Adolescent
Antibody Specificity
Antimicrobial Cationic Peptides
Cathepsin D
Child
Cystic Fibrosis
Glycosaminoglycans
Humans
Hydrolysis
Leukocyte Elastase
Lung
Macromolecular Substances
Molecular Weight
Myeloblastin
Nebulizers and Vaporizers
Protein Precursors
Protein Processing, Post-Translational
Saline Solution, Hypertonic
Solubility
Sputum
Adolescent
Antibody Specificity
Antimicrobial Cationic Peptides
Cathepsin D
Child
Cystic Fibrosis
Glycosaminoglycans
Humans
Hydrolysis
Leukocyte Elastase
Lung
Macromolecular Substances
Molecular Weight
Myeloblastin
Nebulizers and Vaporizers
Protein Precursors
Protein Processing, Post-Translational
Saline Solution, Hypertonic
Solubility
Sputum
Planned Date
Start Date
Collaborators
Principal Investigators
Alternative Titles
Publisher
Abstract
There is an abundance of antimicrobial peptides in cystic fibrosis (CF) lungs. Despite this, individuals with CF are susceptible to microbial colonization and infection. In this study, we investigated the antimicrobial response within the CF lung, focusing on the human cathelicidin LL-37. We demonstrate the presence of the LL-37 precursor, human cathelicidin precursor protein designated 18-kDa cationic antimicrobial protein, in the CF lung along with evidence that it is processed to active LL-37 by proteinase-3. We demonstrate that despite supranormal levels of LL-37, the lung fluid from CF patients exhibits no demonstrable antimicrobial activity. Furthermore Pseudomonas killing by physiological concentrations of exogenous LL-37 is inhibited by CF bronchoalveolar lavage (BAL) fluid due to proteolytic degradation of LL-37 by neutrophil elastase and cathepsin D. The endogenous LL-37 in CF BAL fluid is protected from this proteolysis by interactions with glycosaminoglycans, but while this protects LL-37 from proteolysis it results in inactivation of LL-37 antimicrobial activity. By digesting glycosaminoglycans in CF BAL fluid, endogenous LL-37 is liberated and the antimicrobial properties of CF BAL fluid restored. High sodium concentrations also liberate LL-37 in CF BAL fluid in vitro. This is also seen in vivo in CF sputum where LL-37 is complexed to glycosaminoglycans but is liberated following nebulized hypertonic saline resulting in increased antimicrobial effect. These data suggest glycosaminoglycan-LL-37 complexes to be potential therapeutic targets. Factors that disrupt glycosaminoglycan-LL-37 aggregates promote the antimicrobial effects of LL-37 with the caveat that concomitant administration of antiproteases may be needed to protect the now liberated LL-37 from proteolytic cleavage.
Language
en
ISSN
1550-6606
eISSN
ISBN
DOI
10.4049/jimmunol.0803959
PMID
19542465