The role of STING signaling in central nervous system infection and neuroinflammatory disease

Abstract

The cyclic guanosine monophosphate-adenosine monophosphate (GMP-AMP) synthase-Stimulator of Interferon Genes (cGAS-STING) pathway is a critical innate immune mechanism for detecting the presence of double-stranded DNA (dsDNA) and prompting a robust immune response. Canonical cGAS-STING activation occurs when cGAS, a predominantly cytosolic pattern recognition receptor, binds microbial DNA to promote STING activation. Upon STING activation, transcription factors enter the nucleus to cause the production of Type I interferons, inflammatory cytokines whose primary function is to prime the host for viral infection by producing a number of antiviral interferon-stimulated genes. While the pathway was originally described in viral infection, more recent studies have implicated cGAS-STING signaling in a number of different contexts, including autoimmune disease, cancer, injury, and neuroinflammatory disease. This review focuses on how our understanding of the cGAS-STING pathway has evolved over time with an emphasis on the role of STING-mediated neuroinflammation and infection in the nervous system. We discuss recent findings on how STING signaling contributes to the pathology of pain, traumatic brain injury, and stroke, as well as how mitochondrial DNA may promote STING activation in common neurodegenerative diseases. We conclude by commenting on the current knowledge gaps that should be filled before STING can be an effective therapeutic target in neuroinflammatory disease. This article is categorized under: Neurological Diseases > Molecular and Cellular Physiology Infectious Diseases > Molecular and Cellular Physiology Immune System Diseases > Molecular and Cellular Physiology.

Keywords: STING; brain injury; cGAS; interferons; neuroinflammation; stroke.

FIGURE 1

Mechanism of cGAS-STING signaling. Possible triggers for cGAS-STING signaling discussed in this review are boxed in light blue. DNA binds to cGAS to facilitate dimerization to produce cyclic dinucleotide 2′,3′-cyclic GMP–AMP (2′,3′-cGAMP). cGAMP binds to STING which promotes its dimerization/oligomerization. COP-II vesicles transport STING to the Golgi to activate TBK1. Dimerized TBK1 then phosphorylates IRF3 for nuclear translocation for the transcription of IFN-responsive genes. Created with BioRender.com

FIGURE 2

Following a stroke or TBI, cGAS-STING signaling in resident microglia is activated, likely at least in part due to the presence of mitochondrial DNA. Microglia subsequently produce interferons (primarily IFNβ) and chemokines that result in the infiltration of peripheral immune cells. Once present, these immune cells are also activated and produce additional interferons. Interferons produced by all cell types can bind both their own and other cells’ IFN receptors, IFNAR, including neurons and astrocytes, resulting in increased IFN signaling. Created with BioRender.com