ROS-induced ATF3 causes susceptibility to secondary infections during sepsis-associated immunosuppression
| Autor: | Kerstin Fuchs, Manfred Kneilling, Kamran Ghoreschi, Kyu-Won Kim, Ji-Hyeon Park, Nadejda Valtcheva, Tsonwin Hai, Jürgen Brück, Martin Röcken, Anna Teske, Wolfram Hoetzenecker, Bernd Echtenacher, Konrad Hoetzenecker, Tilo Biedermann, Emmanuella Guenova, Petra Hoffmann, Florian Woelbing, Claus G. Krenn, Kyu Han Kim |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2011 |
| Předmět: |
NF-E2-Related Factor 2
medicine.medical_treatment Secondary infection General Biochemistry Genetics and Molecular Biology Monocytes Article Proinflammatory cytokine Immune tolerance Sepsis 03 medical and health sciences Mice 0302 clinical medicine medicine Immune Tolerance Animals Humans Interleukin 6 Transcription factor 030304 developmental biology 0303 health sciences ATF3 Activating Transcription Factor 3 biology Coinfection Interleukin-6 Immunosuppression General Medicine medicine.disease Glutathione Shock Septic 3. Good health Mice Inbred C57BL Oxidative Stress Gene Expression Regulation 030220 oncology & carcinogenesis Immunology biology.protein Macrophages Peritoneal Female Reactive Oxygen Species Signal Transduction |
| Zdroj: | Nature Medicine; Vol 18 |
| ISSN: | 1078-8956 |
| DOI: | 10.1038/nm.2557 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|