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Originally published online as doi:10.2353/ajpath.2009.080746 on March 5, 2009

Published online before print March 5, 2009
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(American Journal of Pathology. 2009;174:1338-1346.)
© 2009 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2009.080746

Trappin-2 Promotes Early Clearance of Pseudomonas aeruginosa through CD14-Dependent Macrophage Activation and Neutrophil Recruitment

Thomas S. Wilkinson*, Kevin Dhaliwal*, Thomas W. Hamilton*, Alexander F. Lipka{dagger}, Lesley Farrell*, Donald J. Davidson*, Rodger Duffin*, Andrew Conway Morris*, Chris Haslett*, John R.W. Govan{ddagger}§, Christopher D. Gregory*, Jean-Michel Sallenave and A. John Simpson*

From the Medical Research Council, Centre for Inflammation Research,* the Queen’s Medical Research Institute,{ddagger} and the Cystic Fibrosis Group,§ University of Edinburgh, Edinburgh, United Kingdom; the Department of Pulmonology,{dagger} Leiden University Hospital, Leiden, The Netherlands; and the Unit de Défense Innée et Inflammation, INSERM E336, Bâtiment Metchnikoff, Institut Pasteur, Paris, France

Microaspiration of Pseudomonas aeruginosa contributes to the pathogenesis of nosocomial pneumonia. Trappin-2 is a host defense peptide that assists with the clearance of P. aeruginosa through undefined mechanisms. A model of macrophage interactions with replicating P. aeruginosa (strain PA01) in serum-free conditions was developed, and the influence of subantimicrobial concentrations of trappin-2 was subsequently studied. PA01 that was pre-incubated with trappin-2 (at concentrations that have no direct antimicrobial effects), but not control PA01, was cleared by alveolar and bone marrow-derived macrophages. However, trappin-2-enhanced clearance of PA01 was completely abrogated by CD14- null macrophages. Fluorescence microscopy demonstrated the presence of trappin-2 on the bacterial cell surface of trappin-2-treated PA01. In a murine model of early lung infection, trappin-2-treated PA01 was cleared more efficiently than control PA01 2 hours of intratracheal instillation. Furthermore, trappin-2-treated PA01 up-regulated the murine chemokine CXCL1/KC after 2 hours with a corresponding increase in neutrophil recruitment 1 hour later. These in vivo trappin-2-treated PA01 effects were absent in CD14-deficient mice. Trappin-2 appears to opsonize P. aeruginosa for more efficient, CD14-dependent clearance by macrophages and contributes to the induction of chemokines that promote neutrophil recruitment. Trappin-2 may therefore play an important role in innate recognition and clearance of pathogens during the very earliest stages of pulmonary infection.




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