title: Extracellular superoxide dismutase inhibits innate immune responses and clearance of an intracellular bacterial infection.
abstract: Reactive oxygen species and reactive nitrogen species play important roles during immune responses to bacterial pathogens. Extracellular superoxide dismutase (ecSOD) regulates extracellular concentrations of reactive oxygen species and reactive nitrogen species and contributes to tissue protection during inflammatory insults. The participation of ecSOD in immune responses seems therefore intuitive, yet is poorly understood. In the current study, we used mice with varying levels of ecSOD activity to investigate the involvement of this enzyme in immune responses against Listeria monocytogenes. Surprisingly, our data demonstrate that despite enhanced neutrophil recruitment to the liver, ecSOD activity negatively affected host survival and bacterial clearance. Increased ecSOD activity was accompanied by decreased colocalization of neutrophils with bacteria, as well as increased neutrophil apoptosis, which reduced overall and neutrophil-specific TNF-α production. Liver leukocytes from mice lacking ecSOD produced equivalent NO· compared with liver leukocytes from mice expressing ecSOD. However, during infection, there were higher levels of peroxynitrite (NO(3)·(-)) in livers from mice lacking ecSOD compared with livers from mice expressing ecSOD. Neutrophil depletion studies revealed that high levels of ecSOD activity resulted in neutrophils with limited protective capacity, whereas neutrophils from mice lacking ecSOD provided superior protection compared with neutrophils from wild-type mice. Taken together, our data demonstrate that ecSOD activity reduces innate immune responses during bacterial infection and provides a potential target for therapeutic intervention.
authors.affiliation: Department of Molecular Biology and Immunology, University of North Texas Health Science Center, Fort Worth, TX 76107, USA.
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Break
authors.forename: Sujung
authors.initials: S
authors.lastname: Jun
authors.forename: Mohanalaxmi
authors.initials: M
authors.lastname: Indramohan
authors.forename: Karen D
authors.initials: KD
authors.lastname: Carr
authors.forename: Amy N
authors.initials: AN
authors.lastname: Sieve
authors.forename: Ladislav
authors.initials: L
authors.lastname: Dory
authors.forename: Rance E
authors.initials: RE
authors.lastname: Berg
mesh_terms: D000818:Animals; D017209:Apoptosis; D002634:Chemotaxis, Leukocyte; D004198:Disease Susceptibility; D004790:Enzyme Induction; D005260:Female; D054884:Host-Pathogen Interactions / Q000276:immunology*; D007113:Immunity, Innate / Q000276:immunology*; D008089:Listeria monocytogenes / Q000276:immunology* / Q000302:isolation & purification; D008088:Listeriosis / Q000150:complications / Q000276:immunology*; D008099:Liver / Q000737:chemistry / Q000201:enzymology / Q000382:microbiology; D016131:Lymphocyte Subsets / Q000276:immunology; D008297:Male; D051379:Mice; D020297:Mice, Congenic; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009503:Neutropenia / Q000150:complications / Q000276:immunology; D009504:Neutrophils / Q000276:immunology*; D009569:Nitric Oxide / Q000378:metabolism; D030421:Peroxynitrous Acid / Q000378:metabolism; D026361:Reactive Nitrogen Species / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D013154:Spleen / Q000737:chemistry / Q000201:enzymology / Q000382:microbiology; D013482:Superoxide Dismutase / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D026361:Reactive Nitrogen Species; D017382:Reactive Oxygen Species; D014409:Tumor Necrosis Factor-alpha; D030421:Peroxynitrous Acid; D009569:Nitric Oxide; C499090:Sod3 protein, mouse; D013482:Superoxide Dismutase