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

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

Author information

Department of Immunology, University of Washington, Seattle, WA 98109.
Molecular and Cellular Biology Program, University of Washington, Seattle, WA 98195; and.
Immunity, Inflammation, and Disease Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, Durham, NC 27709.
Department of Immunology, University of Washington, Seattle, WA 98109;


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.

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