title: Sulfiredoxin protects mice from lipopolysaccharide-induced endotoxic shock.
abstract: Peroxiredoxins constitute a major family of cysteine-based peroxide-scavenging enzymes. They carry an intriguing redox switch by undergoing substrate-mediated inactivation via overoxidation of their catalytic cysteine to the sulfinic acid form that is reverted by reduction catalyzed by the sulfinic acid reductase sulfiredoxin (Srx). The biological significance of such inactivation is not understood, nor is the function of Srx1. To address this question, we generated a mouse line with a null deletion of the Srx1-encoding Srxn1 gene. We show here that Srxn1(-/-) mice are perfectly viable and do not suffer from any apparent defects under laboratory conditions, but have an abnormal response to lipopolysaccharide that manifests by increased mortality during endotoxic shock. Microarray-based mRNA profiles show that although the response of Srxn1(-/-) mice to lipopolysaccharide is typical, spanning all spectrum and all pathways of innate immunity, it is delayed by several hours and remains intense when the response of Srxn1(+/+) mice has already dissipated. These data indicate that Srx1 activity protects mice from the lethality of endotoxic shock, adding this enzyme to other host factors, as NRF2 and peroxiredoxin 2, which by regulating cellular reactive oxygen species levels act as important modifiers in the pathogenesis of sepsis.
authors.affiliation: CEA, DSV, IBITECS Laboratoire Stress Oxydants et Cancer , Gif-sur-Yvette, France.
authors.forename: Anne-Gaëlle
authors.initials: AG
authors.lastname: Planson
authors.forename: Gaël
authors.initials: G
authors.lastname: Palais
authors.forename: Kahina
authors.initials: K
authors.lastname: Abbas
authors.forename: Matthieu
authors.initials: M
authors.lastname: Gerard
authors.forename: Linhdavanh
authors.initials: L
authors.lastname: Couvelard
authors.forename: Agnès
authors.initials: A
authors.lastname: Delaunay
authors.forename: Sylvain
authors.initials: S
authors.lastname: Baulande
authors.forename: Jean-Claude
authors.initials: JC
authors.lastname: Drapier
authors.forename: Michel B
authors.initials: MB
authors.lastname: Toledano
mesh_terms: D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D001219:Aspartate Aminotransferases / Q000097:blood; D002478:Cells, Cultured; D005260:Female; D005818:Genetic Engineering; D018398:Homeodomain Proteins / Q000378:metabolism; D007113:Immunity, Innate; D053208:Kaplan-Meier Estimate; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D050862:Oxidoreductases Acting on Sulfur Group Donors / Q000235:genetics / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D012772:Shock, Septic / Q000276:immunology / Q000378:metabolism*; D015398:Signal Transduction; D014158:Transcription, Genetic
chemical_list: D018398:Homeodomain Proteins; D008070:Lipopolysaccharides; C489936:Prrx1 protein, mouse; C115469:Prrx2 protein, mouse; D017382:Reactive Oxygen Species; D050862:Oxidoreductases Acting on Sulfur Group Donors; C529381:sulfiredoxin protein, mouse; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase