Activation of the STING-Dependent Type I Interferon Response Reduces Microglial Reactivity and Neuroinflammation

Neuron. 2017 Dec 20;96(6):1290-1302.e6. doi: 10.1016/j.neuron.2017.11.032.


Brain aging and neurodegeneration are associated with prominent microglial reactivity and activation of innate immune response pathways, commonly referred to as neuroinflammation. One such pathway, the type I interferon response, recognizes viral or mitochondrial DNA in the cytoplasm via activation of the recently discovered cyclic dinucleotide synthetase cGAS and the cyclic dinucleotide receptor STING. Here we show that the FDA-approved antiviral drug ganciclovir (GCV) induces a type I interferon response independent of its canonical thymidine kinase target. Inhibition of components of the STING pathway, including STING, IRF3, Tbk1, extracellular IFNβ, and the Jak-Stat pathway resulted in reduced activity of GCV and its derivatives. Importantly, functional STING was necessary for GCV to inhibit inflammation in cultured myeloid cells and in a mouse model of multiple sclerosis. Collectively, our findings uncover an unexpected new activity of GCV and identify the STING pathway as a regulator of microglial reactivity and neuroinflammation.

Keywords: STING; experimental autoimmune encephalomyelitis; ganciclovir; microglia; neuroinflammation; type I interferon response.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Animals, Newborn
  • Antiviral Agents / therapeutic use
  • Cells, Cultured
  • Disease Models, Animal
  • Encephalomyelitis, Autoimmune, Experimental / chemically induced
  • Encephalomyelitis, Autoimmune, Experimental / drug therapy
  • Encephalomyelitis, Autoimmune, Experimental / genetics
  • Encephalomyelitis, Autoimmune, Experimental / pathology*
  • Female
  • Freund's Adjuvant / toxicity
  • Ganciclovir / therapeutic use
  • Gene Expression Regulation / drug effects
  • Gene Expression Regulation / genetics*
  • Humans
  • Interferon Type I / metabolism*
  • Male
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Microglia / drug effects
  • Microglia / metabolism*
  • Monocytes / drug effects
  • Myelin-Oligodendrocyte Glycoprotein / immunology
  • Peptide Fragments / immunology
  • Pertussis Toxin / toxicity
  • Signal Transduction / drug effects
  • Signal Transduction / genetics


  • Antiviral Agents
  • Interferon Type I
  • Membrane Proteins
  • Myelin-Oligodendrocyte Glycoprotein
  • Peptide Fragments
  • Sting1 protein, mouse
  • myelin oligodendrocyte glycoprotein (35-55)
  • Freund's Adjuvant
  • Pertussis Toxin
  • Ganciclovir