title: Targeting ADAM17 in leukocytes increases neutrophil recruitment and reduces bacterial spread during polymicrobial sepsis.
abstract: A rapid and robust recruitment of circulating neutrophils at sites of infection is critical for preventing bacterial spread. The efficiency of this process, however, is greatly diminished during sepsis, a severe systemic inflammatory response to infection. The proteolytic activity of a disintegrin and metalloprotease-17 is induced in the cell membrane of leukocytes upon their activation, resulting in the conversion of membrane to soluble TNF-α and the release of assorted receptors from the surface of neutrophils important for their effector functions. We show that conditional knockout mice lacking a disintegrin and metalloprotease-17 in all leukocytes had a survival advantage when subjected to polymicrobial sepsis. Bacteremia and the levels of circulating proinflammatory cytokines, key determinants of sepsis severity, were significantly reduced in conditional a disintegrin and metalloprotease-17 knockout mice during sepsis. Although cecal bacterial microbiota and load were similar in unmanipulated conditional a disintegrin and metalloprotease-17 knockout and control mice, peritoneal spread of bacteria was significantly reduced in conditional a disintegrin and metalloprotease-17 knockout mice following sepsis induction, which was associated with an amplified recruitment of neutrophils. Taken together, our findings suggest that extensive a disintegrin and metalloprotease-17 induction during sepsis may tip the balance between efficient and impaired neutrophil recruitment.
authors.affiliation: Department of Veterinary and Biomedical Sciences, University of Minnesota, St. Paul, Minnesota, USA; and.
authors.forename: Hemant K
authors.initials: HK
authors.lastname: Mishra
authors.affiliation: Department of Veterinary and Biomedical Sciences, University of Minnesota, St. Paul, Minnesota, USA; and.
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Johnson
authors.affiliation: Department of Veterinary Clinical Sciences, University of Minnesota, St. Paul, Minnesota, USA.
authors.forename: Davis M
authors.initials: DM
authors.lastname: Seelig
authors.affiliation: Department of Veterinary and Biomedical Sciences, University of Minnesota, St. Paul, Minnesota, USA; and walch003@umn.edu.
authors.forename: Bruce
authors.initials: B
authors.lastname: Walcheck
mesh_terms: D000072198:ADAM17 Protein / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D000818:Animals; D058491:Bacterial Load; D002432:Cecum / Q000382:microbiology; D002634:Chemotaxis, Leukocyte / Q000502:physiology*; D060085:Coinfection / Q000201:enzymology / Q000276:immunology* / Q000382:microbiology; D016207:Cytokines / Q000097:blood; D004195:Disease Models, Animal; D000069196:Gastrointestinal Microbiome; D007958:Leukocyte Count; D007962:Leukocytes / Q000201:enzymology*; D051379:Mice; D018345:Mice, Knockout; D009504:Neutrophils / Q000276:immunology*; D018805:Sepsis / Q000201:enzymology / Q000276:immunology* / Q000382:microbiology; D013047:Specific Pathogen-Free Organisms
chemical_list: D016207:Cytokines; D000072198:ADAM17 Protein; C000606463:Adam17 protein, mouse
keywords: TACE; inflammation; microbiota