Oxeiptosis, a ROS-induced caspase-independent apoptosis-like cell-death pathway

  • Nat Immunol. 2018 Feb;19(2):130-140. doi: 10.1038/s41590-017-0013-y.
Cathleen Holze  1 ,  Chloé Michaudel  2 ,  Claire Mackowiak  2 ,  Darya A Haas  1 ,  Christian Benda  3 ,  Philipp Hubel  1 ,  Friederike L Pennemann  1 ,  Daniel Schnepf  4  5 ,  Jennifer Wettmarshausen  6  7 ,  Marianne Braun  8 ,  Daisy W Leung  9 ,  Gaya K Amarasinghe  9 ,  Fabiana Perocchi  6  7 ,  Peter Staeheli  4  10 ,  Bernhard Ryffel  2  11 ,  Andreas Pichlmair  12  13  14
Affiliations
  • 1. Innate Immunity Laboratory, Max-Planck Institute of Biochemistry, Martinsried, Munich, Germany.
  • 2. INEM, Experimental Molecular Immunology, UMR7355 CNRS and University, Orleans, France.
  • 3. Department of Structural Cell Biology, Max-Planck Institute of Biochemistry, Martinsried, Munich, Germany.
  • 4. Institute of Virology, University of Freiburg, Freiburg, Germany.
  • 5. Spemann Graduate School of Biology and Medicine, Albert Ludwigs University Freiburg, Freiburg, Germany.
  • 6. Department of Biochemistry, Gene Center Munich, Munich, Germany.
  • 7. Institute for Diabetes and Obesity, Helmholtz Zentrum Munchen, Neuherberg, Germany.
  • 8. EM-Histo Lab, Max-Planck Institute of Neurobiology, Martinsried, Munich, Germany.
  • 9. Department of Pathology and Immunology, Washington University School of Medicine, St Louis, MO, USA.
  • 10. Faculty of Medicine, University of Freiburg, Freiburg, Germany.
  • 11. Institute of Infectious Diseases and Molecular Medicine, University of Cape Town, Cape Town, South Africa.
  • 12. Innate Immunity Laboratory, Max-Planck Institute of Biochemistry, Martinsried, Munich, Germany. [email protected].
  • 13. School of Medicine, Institute of Virology, Technical University of Munich, Munich, Germany. [email protected].
  • 14. German Center for Infection Research (DZIF), Munich partner site, Munich, Germany. [email protected].
PMID: 29255269 DOI: 10.1038/s41590-017-0013-y
Abstract

Reactive oxygen species (ROS) are generated by virus-infected cells; however, the physiological importance of ROS generated under these conditions is unclear. Here we found that the inflammation and cell death induced by exposure of mice or cells to sources of ROS were not altered in the absence of canonical ROS-sensing pathways or known cell-death pathways. ROS-induced cell-death signaling involved interactions among the cellular ROS sensor and antioxidant factor KEAP1, the Phosphatase PGAM5 and the proapoptotic factor AIFM1. Pgam5 -/- mice showed exacerbated lung inflammation and proinflammatory cytokines in an ozone-exposure model. Similarly, challenge with influenza A virus led to increased infiltration of the virus, lymphocytic bronchiolitis and reduced survival of Pgam5 -/- mice. This pathway, which we have called 'oxeiptosis', was a ROS-sensitive, Caspase independent, non-inflammatory cell-death pathway and was important for protection against inflammation induced by ROS or ROS-generating agents such as viral pathogens.