title: ROS-induced ATF3 causes susceptibility to secondary infections during sepsis-associated immunosuppression.
abstract: Sepsis, sepsis-induced hyperinflammation and subsequent sepsis-associated immunosuppression (SAIS) are important causes of death. Here we show in humans that the loss of the major reactive oxygen species (ROS) scavenger, glutathione (GSH), during SAIS directly correlates with an increase in the expression of activating transcription factor 3 (ATF3). In endotoxin-stimulated monocytes, ROS stress strongly superinduced NF-E2-related factor 2 (NRF2)-dependent ATF3. In vivo, this ROS-mediated superinduction of ATF3 protected against endotoxic shock by inhibiting innate cytokines, as Atf3(-/-) mice remained susceptible to endotoxic shock even under conditions of ROS stress. Although it protected against endotoxic shock, this ROS-mediated superinduction of ATF3 caused high susceptibility to bacterial and fungal infections through the suppression of interleukin 6 (IL-6). As a result, Atf3(-/-) mice were protected against bacterial and fungal infections, even under conditions of ROS stress, whereas Atf3(-/-)Il6(-/-) mice were highly susceptible to these infections. Moreover, in a model of SAIS, secondary infections caused considerably less mortality in Atf3(-/-) mice than in wild-type mice, indicating that ROS-induced ATF3 crucially determines susceptibility to secondary infections during SAIS.
authors.affiliation: Department of Dermatology, University Medical Center, Eberhard Karls University Tuebingen, Tuebingen, Germany.
authors.forename: Wolfram
authors.initials: W
authors.lastname: Hoetzenecker
authors.forename: Bernd
authors.initials: B
authors.lastname: Echtenacher
authors.forename: Emmanuella
authors.initials: E
authors.lastname: Guenova
authors.forename: Konrad
authors.initials: K
authors.lastname: Hoetzenecker
authors.forename: Florian
authors.initials: F
authors.lastname: Woelbing
authors.forename: Jürgen
authors.initials: J
authors.lastname: Brück
authors.forename: Anna
authors.initials: A
authors.lastname: Teske
authors.forename: Nadejda
authors.initials: N
authors.lastname: Valtcheva
authors.forename: Kerstin
authors.initials: K
authors.lastname: Fuchs
authors.forename: Manfred
authors.initials: M
authors.lastname: Kneilling
authors.forename: Ji-Hyeon
authors.initials: JH
authors.lastname: Park
authors.forename: Kyu-Han
authors.initials: KH
authors.lastname: Kim
authors.forename: Kyu-Won
authors.initials: KW
authors.lastname: Kim
authors.forename: Petra
authors.initials: P
authors.lastname: Hoffmann
authors.forename: Claus
authors.initials: C
authors.lastname: Krenn
authors.forename: Tsonwin
authors.initials: T
authors.lastname: Hai
authors.forename: Kamran
authors.initials: K
authors.lastname: Ghoreschi
authors.forename: Tilo
authors.initials: T
authors.lastname: Biedermann
authors.forename: Martin
authors.initials: M
authors.lastname: Röcken
mesh_terms: D051700:Activating Transcription Factor 3 / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D060085:Coinfection / Q000276:immunology* / Q000382:microbiology; D005260:Female; D005786:Gene Expression Regulation; D005978:Glutathione / Q000097:blood / Q000378:metabolism*; D006801:Humans; D007108:Immune Tolerance; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism*; D017737:Macrophages, Peritoneal / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D009000:Monocytes / Q000378:metabolism; D051267:NF-E2-Related Factor 2 / Q000378:metabolism; D018384:Oxidative Stress; D017382:Reactive Oxygen Species / Q000097:blood / Q000378:metabolism*; D012772:Shock, Septic / Q000276:immunology* / Q000378:metabolism; D015398:Signal Transduction
chemical_list: C490449:ATF3 protein, human; D051700:Activating Transcription Factor 3; C103002:Atf3 protein, mouse; D015850:Interleukin-6; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; D017382:Reactive Oxygen Species; D005978:Glutathione