Intracellular Nucleic Acid Sensing Triggers Necroptosis through Synergistic Type I IFN and TNF Signaling

J Immunol. 2018 Apr 15;200(8):2748-2756. doi: 10.4049/jimmunol.1701492. Epub 2018 Mar 14.


The sensing of viral nucleic acids within the cytosol is essential for the induction of innate immune responses following infection. However, this sensing occurs within cells that have already been infected. The death of infected cells can be beneficial to the host by eliminating the virus's replicative niche and facilitating the release of inflammatory mediators. In this study, we show that sensing of intracellular DNA or RNA by cGAS-STING or RIG-I-MAVS, respectively, leads to activation of RIPK3 and necroptosis in bone marrow-derived macrophages. Notably, this requires signaling through both type I IFN and TNF receptors, revealing synergy between these pathways to induce cell death. Furthermore, we show that hyperactivation of STING in mice leads to a shock-like phenotype, the mortality of which requires activation of the necroptotic pathway and IFN and TNF cosignaling, demonstrating that necroptosis is one outcome of STING signaling in vivo.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Cell Death / physiology*
  • DNA, Viral / immunology
  • Immunity, Innate / immunology
  • Interferon Type I / immunology
  • Interferon Type I / metabolism*
  • Membrane Proteins / immunology
  • Membrane Proteins / metabolism
  • Mice
  • RNA, Viral / immunology
  • Signal Transduction / immunology*
  • Tumor Necrosis Factor-alpha / immunology
  • Tumor Necrosis Factor-alpha / metabolism*
  • Virus Diseases / immunology


  • DNA, Viral
  • Interferon Type I
  • Membrane Proteins
  • RNA, Viral
  • Sting1 protein, mouse
  • Tumor Necrosis Factor-alpha