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* Institut National de la Santé et de la Recherche Médicale, Programme Avenir, IFR53, University of Reims Champagne-Ardenne, Reims, France;
Department of Radiology, Washington University School of Medicine, St. Louis, MO 63110; and
Department of Microbiology and Immunology, University of British Columbia, Vancouver, Canada
According to the widely accepted view, neutrophil elastase (NE), a neutrophil-specific serine protease, is a major contributor to Pseudomonas aeruginosa infection-associated host tissue inflammation and damage, which in severe cases can lead to death. Herein, we provide for the first time compelling evidence that the host rather employs NE to protect itself against P. aeruginosa infection. Using a clinically relevant model of pneumonia, targeted deficiency in NE increased the susceptibility of mice to P. aeruginosa. We found that NE was required for maximal intracellular killing of P. aeruginosa by neutrophils. In investigating the mechanism of NE-mediated killing of P. aeruginosa, we found that NE degraded the major outer membrane protein F, a protein with important functions, including porin activity, maintenance of structural integrity, and sensing of host immune system activation. Consistent with this, the use of an isogenic mutant deficient in outer membrane protein F negated the role of NE in host defense against P. aeruginosa infection.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by grants from Conseil Régional Champagne-Ardenne, Institut National de la Santé et de la Recherche Médicale, Programme Avenir (to R.B. and A.B.), Fondation pour la Recherche Médicale, and Agence Nationale de la Recherche (to A.B.), and Canadian Institutes of Health Research (to R.E.H., who holds a Canada Research Chair).
2 Current address: Department of Pulmonary Medicine, University Hospital Frankfurt, Frankfurt 60590, Germany.
3 T.O.H. and R.B. contributed equally to this paper.
4 Address correspondence and reprint requests to Dr. Azzaq Belaaouaj, Institut National de la Santé et de la Recherche Médicale, Hôpital Inflammation and Immunity of the Respiratory Epithelium Group, Centre Hospitalier Universitaire de Reims IFR53, 45, rue Cognacq Jay, Maison Blancher, Reims 51092, France. E-mail address: azzaq.belaaouaj{at}univ-reims.fr
5 Abbreviations used in this paper: NE, neutrophil elastase; 
1-AT, 1-antitrypsin; AEBSF, 4-(2-aminoethyl)benzenesulfonyl fluoride hydrochloride; BAL, bronchoalveolar lavage; CG, cathepsin G; CI, competitive killing index; IEF, isoelectric focusing; i.n., intranasal; MMP, metalloproteinase; MPO, myeloperoxidase; NPN, 1-N-phenylnaphthylamine; Om, outer membrane; Omps, outer membrane proteins; OprF, outer membrane protein F; SEM, scanning electron microscopy; SLPI, secretory leukocyte protease inhibitor; TEM, transmission electron microscopy; WT, wild type.
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