ROS-induced ATF3 causes susceptibility to secondary infections during sepsis-associated immunosuppression.

Details

Serval ID
serval:BIB_A7FEDC1F1E50
Type
Article: article from journal or magazin.
Collection
Publications
Title
ROS-induced ATF3 causes susceptibility to secondary infections during sepsis-associated immunosuppression.
Journal
Nature medicine
Author(s)
Hoetzenecker W., Echtenacher B., Guenova E. (co-first), Hoetzenecker K., Woelbing F., Brück J., Teske A., Valtcheva N., Fuchs K., Kneilling M., Park J.H., Kim K.H., Kim K.W., Hoffmann P., Krenn C., Hai T., Ghoreschi K., Biedermann T., Röcken M.
ISSN
1546-170X (Electronic)
ISSN-L
1078-8956
Publication state
Published
Issued date
18/12/2011
Peer-reviewed
Oui
Volume
18
Number
1
Pages
128-134
Language
english
Notes
Publication types: Journal Article ; Research Support, Non-U.S. Gov't
Publication Status: epublish
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.
Keywords
Activating Transcription Factor 3/genetics, Activating Transcription Factor 3/metabolism, Animals, Coinfection/immunology, Coinfection/microbiology, Female, Gene Expression Regulation, Glutathione/blood, Glutathione/metabolism, Humans, Immune Tolerance, Interleukin-6/genetics, Interleukin-6/metabolism, Macrophages, Peritoneal/immunology, Mice, Mice, Inbred C57BL, Monocytes/metabolism, NF-E2-Related Factor 2/metabolism, Oxidative Stress, Reactive Oxygen Species/blood, Reactive Oxygen Species/metabolism, Shock, Septic/immunology, Shock, Septic/metabolism, Signal Transduction
Pubmed
Web of science
Create date
27/08/2020 14:00
Last modification date
27/10/2020 21:23
Usage data