Format

Send to

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

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

Author information

1
Department of Neurology and Neurological Sciences, School of Medicine, Stanford University, Stanford, CA 94305, USA; Center for Tissue Regeneration, Repair and Rehabilitation, VA Palo Alto Health Care System, Palo Alto, CA 94304, USA.
2
Laboratory of Molecular and Chemical Biology of Neurodegeneration, Brain Mind Institute, Station 19, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne (EPFL), CH-1015 Lausanne, Switzerland.
3
Chemical Engineering Graduate Program, School of Engineering, Stanford University, Stanford, CA 94305, USA.
4
Department of Neurology and Neurological Sciences, School of Medicine, Stanford University, Stanford, CA 94305, USA.
5
Center for Tissue Regeneration, Repair and Rehabilitation, VA Palo Alto Health Care System, Palo Alto, CA 94304, USA.
6
Institute for Memory Impairments and Neurological Disorders, University of California, Irvine, Irvine, CA 92697, USA.
7
Biochemistry Department, School of Medicine, Stanford University, Stanford, CA 94305, USA.
8
Department of Neurology and Neurological Sciences, School of Medicine, Stanford University, Stanford, CA 94305, USA; Center for Tissue Regeneration, Repair and Rehabilitation, VA Palo Alto Health Care System, Palo Alto, CA 94304, USA. Electronic address: twc@stanford.edu.

Abstract

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

Supplemental Content

Full text links

Icon for Elsevier Science Icon for PubMed Central
Loading ...
Support Center