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

Hoetzenecker W. et al., Nat Med. 2012. 18:128-134.

Speaker：Yu-Chang Chang (張育菖)                                               Time：13:10~14:00, Mar. 21, 2012

Commentator：Chi-Chang Shieh, M.D., Ph.D. (謝奇璋 老師)     Place：Room 601

Abstract:

Sepsis is a medical condition characterized by a systemic inflammatory response syndrome and the presence of a known or suspected infection. Sepsis and sepsis-associated immunosuppression (SAIS) are important causes of death ¹. The authors found that patients during SAIS showed loss of the major reactive oxygen species (ROS) scavenger, glutathione (GSH), which correlated with an increased activating transcription factor 3 (ATF3) and a decreased serum interleukin 6 (IL-6). To selectively mimic ROS stress during SAIS, the authors depleted GSH in human monocytes and then stimulated them with lipopolysaccharide (LPS). In LPS-stimulated monocytes, ROS stress strongly superinduced NF-E2-related factor 2-dependent ATF3 expression. In vivo, ROS-mediated ATF3 superinduction inhibited LPS-induced innate cytokine production, which protected mice against LPS-induced lethal shock. However, ATF3-mediated suppression of IL-6 caused high susceptibility to bacterial and fungal infections. As a result, Atf3^-/- mice were protected against bacterial and fungal infections, whereas Atf3^-/- IL-6^-/- mice were more susceptible to these infections. Besides, in a well-established mouse model of SAIS ², the authors found that all wild-type mice died from secondary infection, whereas 20% of the Atf3^-/- mice survived from this challenge, indicating that ROS-induced ATF3 caused susceptibility to secondary infections during SAIS. In conclusion, ATF3 superinduction protects against endotoxic shock by inhibiting innate cytokine storm, however, ATF3-mediated IL-6 suppression abrogates the control of bacteria and fungi, and causes high susceptibility to secondary infection.

References:

1.    Riedemann NC, Guo RF, Ward PA. Novel strategies for the treatment of sepsis. Nat Med. 2003 9:517-24

2.    Benjamim CF, Hogaboam CM, Kunkel SL. The chronic consequences of severe sepsis. J Leukoc Biol. 2004 75:408-12