title: Neutrophil elastase modulates cytokine expression: contribution to host defense against Pseudomonas aeruginosa-induced pneumonia.
abstract: There is accumulating evidence that following bacterial infection, the massive recruitment and activation of the phagocytes, neutrophils, is accompanied with the extracellular release of active neutrophil elastase (NE), a potent serine protease. Using NE-deficient mice in a clinically relevant model of Pseudomonas aeruginosa-induced pneumonia, we provide compelling in vivo evidence that the absence of NE was associated with decreased protein and transcript levels of the proinflammatory cytokines TNF-α, MIP-2, and IL-6 in the lungs, coinciding with increased mortality of mutant mice to infection. The implication of NE in the induction of cytokine expression involved at least in part Toll-like receptor 4 (TLR-4). These findings were further confirmed following exposure of cultured macrophages to purified NE. Together, our data suggest strongly for the first time that NE not only plays a direct antibacterial role as it has been previously reported, but released active enzyme can also modulate cytokine expression, which contributes to host protection against P. aeruginosa. In light of our findings, the long held view that considers NE as a prime suspect in P. aeruginosa-associated diseases will need to be carefully reassessed. Also, therapeutic strategies aiming at NE inhibition should take into account the physiologic roles of the enzyme.
authors.affiliation: Inserm Avenir Program, CHU de Reims, Maison Blanche, Reims 51092, France; EA 4303, Inflammation and Immunity of the Respiratory Epithelium, CHU de Reims, Maison Blanche, Reims 51092, France.
authors.forename: Rym
authors.initials: R
authors.lastname: Benabid
authors.affiliation: Inserm Avenir Program, CHU de Reims, Maison Blanche, Reims 51092, France; EA 4303, Inflammation and Immunity of the Respiratory Epithelium, CHU de Reims, Maison Blanche, Reims 51092, France.
authors.forename: Julien
authors.initials: J
authors.lastname: Wartelle
authors.affiliation: Inserm Avenir Program, CHU de Reims, Maison Blanche, Reims 51092, France; EA 4303, Inflammation and Immunity of the Respiratory Epithelium, CHU de Reims, Maison Blanche, Reims 51092, France.
authors.forename: Laurette
authors.initials: L
authors.lastname: Malleret
authors.affiliation: Inserm Avenir Program, CHU de Reims, Maison Blanche, Reims 51092, France; EA 4303, Inflammation and Immunity of the Respiratory Epithelium, CHU de Reims, Maison Blanche, Reims 51092, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Guyot
authors.affiliation: EA 4303, Inflammation and Immunity of the Respiratory Epithelium, CHU de Reims, Maison Blanche, Reims 51092, France.
authors.forename: Sophie
authors.initials: S
authors.lastname: Gangloff
authors.affiliation: Inserm Avenir Program, CHU de Reims, Maison Blanche, Reims 51092, France; EA 4303, Inflammation and Immunity of the Respiratory Epithelium, CHU de Reims, Maison Blanche, Reims 51092, France.
authors.forename: François
authors.initials: F
authors.lastname: Lebargy
authors.affiliation: Inserm Avenir Program, CHU de Reims, Maison Blanche, Reims 51092, France; EA 4303, Inflammation and Immunity of the Respiratory Epithelium, CHU de Reims, Maison Blanche, Reims 51092, France. Electronic address: azzaq.belaaouaj@univ-reims.fr.
authors.forename: Azzaq
authors.initials: A
authors.lastname: Belaaouaj
mesh_terms: D000818:Animals; D016207:Cytokines / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology*; D005786:Gene Expression Regulation / Q000276:immunology*; D007113:Immunity, Innate; D019272:Leukocyte Elastase / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D008168:Lung / Q000201:enzymology / Q000276:immunology / Q000382:microbiology / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D018410:Pneumonia, Bacterial / Q000201:enzymology / Q000235:genetics / Q000276:immunology* / Q000382:microbiology / Q000473:pathology; D011552:Pseudomonas Infections / Q000201:enzymology / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D011550:Pseudomonas aeruginosa / Q000276:immunology* / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000276:immunology / Q000378:metabolism
chemical_list: D016207:Cytokines; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D019272:Leukocyte Elastase