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

Publication

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

Journal Paper/Review - Dec 18, 2011

Hoetzenecker Wolfram, Biedermann Tilo, Ghoreschi Kamran, Hai Tsonwin, Krenn Claus, Hoffmann Petra, Kim Kyu-Won, Kim Kyu-Han, Park Ji-Hyeon, Kneilling Manfred, Fuchs Kerstin, Valtcheva Nadejda, Teske Anna, Brück Jürgen, Woelbing Florian, Hoetzenecker Konrad, Guenova Emmanuella, Echtenacher Bernd, Röcken Martin

Citation

Hoetzenecker W, Biedermann T, Ghoreschi K, Hai T, Krenn C, Hoffmann P, Kim K, Kim K, Park J, Kneilling M, Fuchs K, Valtcheva N, Teske A, Brück J, Woelbing F, Hoetzenecker K, Guenova E, Echtenacher B, Röcken M. ROS-induced ATF3 causes susceptibility to secondary infections during sepsis-associated immunosuppression. Nat Med 2011; 18:128-34.

Type

Journal Paper/Review (English)

Journal

Nat Med 2011; 18

Publication Date

Dec 18, 2011

Issn Electronic

1546-170X

Pages

128-34

Brief description/objective

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.