Myeloperoxidase Plays Critical Roles in Killing Klebsiella pneumoniae and Inactivating Neutrophil Elastase: Effects on Host Defense

• Published in: The Journal of immunology (1950) 2005-02, Vol.174 (3), p.1557-1565
• Main Authors: Hirche, Tim O, Gaut, Joseph P, Heinecke, Jay W, Belaaouaj, Azzaq
• Format: Article
• Language: English
• Subjects: Animals; Blood Bactericidal Activity - immunology; Humans; Hypochlorous Acid - blood; Hypochlorous Acid - pharmacology; Immunity, Innate - genetics; Inflammation Mediators - antagonists & inhibitors; Inflammation Mediators - physiology; Intracellular Fluid - enzymology; Intracellular Fluid - immunology; Intracellular Fluid - microbiology; Klebsiella Infections - enzymology; Klebsiella Infections - immunology; Klebsiella Infections - mortality; Klebsiella Infections - prevention & control; Klebsiella pneumoniae; Klebsiella pneumoniae - growth & development; Klebsiella pneumoniae - immunology; Leukocyte Elastase - antagonists & inhibitors; Leukocyte Elastase - blood; Leukocyte Elastase - deficiency; Leukocyte Elastase - genetics; Mice; Mice, Inbred C57BL; Mice, Knockout; Neutrophil Activation - immunology; Neutrophils - enzymology; Neutrophils - immunology; Neutrophils - microbiology; Peroxidase - blood; Peroxidase - deficiency; Peroxidase - genetics; Peroxidase - physiology; Protease Inhibitors - blood; Protease Inhibitors - pharmacology; Reactive Oxygen Species - blood; Reactive Oxygen Species - pharmacology
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.174.3.1557

Activated neutrophils use myeloperoxidase (MPO) to generate an array of potent toxic oxidants. In the current studies we used genetically altered mice deficient in MPO to investigate the role of the enzyme in host defense against the Gram-negative bacterium Klebsiella pneumoniae, an important human pathogen. For comparison, we used mice deficient in the antimicrobial molecule, neutrophil elastase (NE). When challenged i.p., mice deficient in either MPO or NE were markedly more susceptible to bacterial infection and death. In vitro studies suggested that MPO impairs the morphology of bacteria in a distinctive way. Of importance, our in vitro studies found that MPO mediated oxidative inactivation of NE, an enzyme that has been widely implicated in the pathogenesis of various tissue-destructive diseases. This pathway of oxidative inactivation may be physiologically relevant, because activated neutrophils isolated from MPO-deficient mice exhibited increased elastase activity. Our observations provide strong evidence that MPO, like NE, is a key player in the killing of K. pneumoniae bacteria. They also suggest that MPO may modulate NE to protect the host from the tissue-degrading activity of this proteinase.