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

Publisher Website
Google Scholar
Abstract
Sepsis is associated with a hyperinduction of proinflammatory cytokines. ATF3, a transcription factor, is induced in macrophages under conditions of endotoxic shock and downregulates expression of cytokines, including interleukin-6 (IL-6). Although ATF3 may thereby mitigate the severity of sepsis, Hoetzenecker et al. now show that endotoxin-induced ATF3 increases the susceptibility of mice to secondary pathogenic infections due to suppression of IL-6. Their findings suggest that temporal modulation of ATF3 may be important for the successful resolution of sepsis and the ensuing sepsis-associated immunosuppression. 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.