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Serine Protease Inhibitor 6-Deficient Mice Have Increased Neutrophil Immunity to Pseudomonas aeruginosa¹

Manling Zhang^*,, Ni Liu^*,, Sun-Mi Park, Yue Wang^*,, Susan Byrne, Andrea E. Murmann, Scott Bahr^¶, Marcus E. Peter, Steven T. Olson^||, Abderrazzaq Belaaouaj^¶ and Philip G. Ashton-Rickardt^2,*,,

^* Department of Pathology, Ben May Institute for Cancer Research, Committee on Immunology, Department of Medicine, University of Chicago, Chicago, IL 60637; ^¶ Institut National de la Santé et de la Recherche Médicale Unité Mixte de Recherche en Santé, Reims, France; and ^|| Center for Molecular Biology of Oral Diseases, University of Illinois at Chicago, Chicago, IL 60612

Inflammation is a localized, protective response to trauma or microbial invasion that destroys the injurious agent and the injured tissue. Neutrophil elastase (NE), a serine protease stored in the azurophil granules of polymorphonuclear neutrophils, digests microbes after phagocytosis. NE can also digest microbes extracellularly but is associated with tissue damage and inflammatory disease. In this study, we show that polymorphonuclear neutrophils from mice deficient in serine protease inhibitor 6, a weak intracellular NE inhibitor, had increased susceptibility to self-inflicted lysis because of increased NE activity. The resulting transient increase in local extracellular NE activity was within a narrow range that resulted in the clearance of Pseudomonas aeruginosa but did not damage the lung. Therefore, deficiency in a weak intracellular inhibitor of NE results in an acute inflammatory response that protects from P. aeruginosa but does not cause lung disease.

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 National Institutes of Health Grant AI45108 (to P.G.A-R.).

² Address correspondence and reprint requests to Dr. P. G. Ashton-Rickardt, Department of Immunology, Division of Medicine, Imperial College London, Hammersmith Campus, Du Cane Road, London, U.K. E-mail: p.ashton-rickardt{at}imperial.ac.uk

³ Abbreviations used in this paper: PMN, polymorphonuclear neutrophils; Spi, serine protease inhibitor; NE, neutrophil elastase; SI, stoichiometry of the inhibition; HNE, human NE; KO, knockout; GrB, granzyme B; LDH, lactate dehydrogenase; PI, propidioum iodide; COPD, chronic pulmonary obstructive disease; Cat G, cathepsin G; TG, thioglycollate; WT, wild type; GST, glutathione transferase; BAL, bronchoalveolar lavage; i.n., intranasally; LB, Luria-Bertani.