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.

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Acknowledgements

We thank B. Pichler, N. Suttorp, T. Welte, S. Werner and P. Dotto for helpful discussions, and for reviewing the manuscript, and M. Haberbosch and S. Hemberger for technical assistance. S. Werner (Eidgenössische Technische Hochschule Zürich) provided the Nrf2−/− (Nfe2l2tm1Ywk) mice25 with the permission of J.A. Johnson (University of California, San Francisco). This work has been supported by grants from the Sander Stiftung (2005.043.2 and 2005.043.3), Deutsche Krebshilfe (no. 109037), Deutsche Forschungsgemeinschaft (SFB 685 A6 and C1, Bi 696/3-3, Bi 696/5-1), German Federal Ministry of Education and Research (BMBF FKZ 0315079 to K.G., DLR 01GN0970 to M.R.), University of Tuebingen (W.H., f-33654-87; E.G., f-1803-0-0; K.G. and M.R., IZKF-Tuebingen, collaborative research program), European Union FP7-HEALTH-2007-2.4.4-1 200515 (M.R.), The German Dermatologic Society/Arbeitsgemeinschaft Dermatologische Forschung (W.H.), a National Research Foundation of Korea grant that was funded by the Ministry of Education, Science and Technology through the Creative Research Initiative Program (grant R16-2004-001010010,2010) and a World Class University grant (no. R31-2008-000-10103-0).

Author information

Author notes

    • Wolfram Hoetzenecker
    • , Bernd Echtenacher
    •  & Emmanuella Guenova

    These authors contributed equally to this work.

Affiliations

  1. Department of Dermatology, University Medical Center, Eberhard Karls University Tuebingen, Tuebingen, Germany.

    • Wolfram Hoetzenecker
    • , Emmanuella Guenova
    • , Florian Woelbing
    • , Jürgen Brück
    • , Anna Teske
    • , Kerstin Fuchs
    • , Manfred Kneilling
    • , Kamran Ghoreschi
    • , Tilo Biedermann
    •  & Martin Röcken
  2. Institute of Immunology, University of Regensburg, Regensburg, Germany.

    • Bernd Echtenacher
  3. Department of Surgery, Medical University of Vienna, Vienna, Austria.

    • Konrad Hoetzenecker
  4. Institute of Pharmaceutical Sciences, Pharmacogenomics, Swiss Federal Institute of Technology, Zurich, Switzerland.

    • Nadejda Valtcheva
  5. Laboratory for Preclinical Imaging and Imaging Technology of the Werner Siemens-Foundation, Department for Preclinical Imaging and Radiopharmacy, University Medical Center, Eberhard Karls University Tuebingen, Tuebingen, Germany.

    • Kerstin Fuchs
    •  & Manfred Kneilling
  6. NeuroVascular Coordination Research Center, College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, South Korea.

    • Ji-Hyeon Park
    • , Kyu-Han Kim
    •  & Kyu-Won Kim
  7. Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul National University, Seoul, South Korea.

    • Kyu-Won Kim
  8. Department of Haematology and Oncology, University Hospital Regensburg, Regensburg, Germany.

    • Petra Hoffmann
  9. Department of Anaesthesia and General Intensive Care, Medical University of Vienna, Vienna, Austria.

    • Claus Krenn
  10. Department of Molecular and Cellular Biochemistry, Neurobiotechnology Center, The Ohio State University, Columbus, Ohio, USA.

    • Tsonwin Hai

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Contributions

W.H., B.E., E.G., N.V., A.T. and F.W. performed the experiments and analytical methods (quantitative PCR, western blots, flow cytometry, ELISA, CLP and endotoxin model) and analyzed the data. J.-H.P., K.-H.K. and K.-W.K. performed the luciferase and chromatin immunoprecipitation experiments. K.H. and C.K. collected the blood samples of subjects with sepsis. P.H. measured the bacterial and fungal loads. K.F. and M.K. performed arthritis experiments. J.B., K.G. and M.R. developed the glutathione depletion model in vitro and in vivo and the initial proof of concept. W.H., B.E., E.G., F.W., T.B. and M.R. designed the experiments. W.H., B.E., E.G., F.W., J.B., K.G., T.B. and M.R. discussed the manuscript. M.R. developed the concept. W.H., E.G., B.E. and M.R. coordinated and directed the project. T.H. provided the Atf3−/− mice. W.H., T.B. and M.R. interpreted the data and wrote the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Tilo Biedermann or Martin Röcken.

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DOI

https://doi.org/10.1038/nm.2557

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